6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling

ABSTRACT

Benzoxazole and benzothiazole compounds and the stereoisomers, tautomers, solvates, oxides, esters, and prodrugs thereof and pharmaceutically acceptable salts thereof are disclosed. Compositions of the compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier, and uses of the compounds, either alone or in combination with at least one additional therapeutic agent are also disclosed. The embodiments are useful for inhibiting cellular proliferation, inhibiting the growth and/or metathesis of tumors, treating or preventing cancer, treating or preventing degenerating bone diseases such as rheumatoid arthritis, and/or inhibiting molecules such as CSF-1R.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional and claims the benefit under 35 U.S.C.§120 and 121 of U.S. patent application Ser. No. 11/737,069, filed Apr.18, 2007 now U.S. Pat. No. 7,553,854, which in turn claims the benefitunder 35 U.S.C. §119(e) of U.S. Provisional Application Ser. No.60/793,517, filed Apr. 19, 2006, and No. 60/893,857, filed Mar. 8, 2007.The entire contents of each of these prior applications are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 6-O-substituted benzoxazole andbenzothiazole compounds, their tautomers, stereoisomers, solvates,oxides, esters, metabolites, and prodrugs, and to the pharmaceuticallyacceptable salts thereof. This invention also relates to compositions ofthe compounds together with pharmaceutically acceptable carriers. Inanother aspect, this invention relates to uses of the compounds, eitheralone or in combination with at least one additional therapeutic agent,in the prophylaxis or treatment of cancer.

2. State of the Art

CSF-1R is the receptor for M-CSF (macrophage colony stimulating factor,also called CSF-1) and mediates the biological effects of this cytokine(Sherr 1985). The cloning of the colony stimulating factor-1 receptor(also called c-fms) was described for the first time in Roussel et al.,Nature 325:549-552 (1987). In that publication, it was shown that CSF-1Rhad transforming potential dependent on changes in the C-terminal tailof the protein including the loss of the inhibitory tyrosine 969phosphorylation which binds Cbl and thereby regulates receptor downregulation (Lee 1999).

CSF-1R is a single chain, transmembrane receptor tyrosine kinase (RTK)and a member of the family of immunoglobulin (Ig) motif containing RTKscharacterized by repeated Ig domains in the extracellular portion of thereceptor. The intracellular protein tyrosine kinase domain isinterrupted by a unique insert domain that is also present in the otherrelated RTK class III family members that include the platelet derivedgrowth factor receptors (PDGFR), stem cell growth factor receptor(c-Kit) and fins-like cytokine receptor (FLT3). In spite of thestructural homology among this family of growth factor receptors, theyhave distinct tissue-specific functions. CSF-1R is mainly expressed oncells of the monocytic lineage and in the female reproductive tract andplacenta. In addition expression of CSF-1R has been reported inLangerhans cells in skin, a subset of smooth muscle cells (Inaba 1992),B cells (Baker 1993) and microglia (Sawada 1990).

The main biological effects of CSF-1R signaling are the differentiation,proliferation, migration, and survival of the precursor macrophages andosteoclasts from the monocytic lineage. Activation of CSF-1R is mediatedby its only ligand, M-CSF. Binding of M-CSF to CSF-1R induces theformation of homodimers and activation of the kinase by tyrosinephosphorylation (Stanley 1997). Further signaling is mediated by the p85subunit of PI3K and Grb2 connecting to the PI3K/AKT and Ras/MAPKpathways, respectively. These two important signaling pathways canregulate proliferation, survival and apoptosis. Other signalingmolecules that bind the phosphorylated intracellular domain of CSF-1Rinclude STAT1, STAT3, PLCγ, and Cbl (Bourette 2000).

CSF-1R signaling has a physiological role in immune responses, in boneremodeling and in the reproductive system. The knockout animals foreither M-CSF-1 (op/op mouse; Pollard 1996) or CSF-1R (Dai 2002) havebeen shown to have osteopetrotic, hematopoietic, tissue macrophage, andreproductive phenotypes consistent with a role for CSF-1R in therespective cell types.

The recent success of targeted therapeutics, such as Herceptin® andAvastin®, has underscored the importance in developing “cleaner” lesspromiscuous drugs with a more specific mechanism of action. These drugscan minimize adverse events, have greater predictability, givephysicians greater flexibility in their treatments, and provideresearchers with a better understanding of a particular target.Additionally, targeted therapy may allow treatment of multipleindications affected by the same signaling pathway with fewer andpotentially easier to manage toxicities. (BioCentury, V. 14(10)February, 2006) Inhibition of an individual kinase, such as CSF-1R,which is integrated within a pathway associated with cancer or otherdiseases, can effectively modulate downstream kinases as well, therebyaffecting the entire pathway. However, the active sites of 491 humanprotein kinase domains are highly conserved, which makes the design ofselective inhibitors a formidable challenge (Cohen 2005). Accordingly,there is a need for selective kinase inhibitors, such as selectiveCSF-1R inhibitors.

SUMMARY OF THE INVENTION

A continuing need exists for compounds that inhibit cellularproliferation, inhibit the growth of tumors, treat cancer, modulate cellcycle arrest, and/or specifically inhibit molecules such as CSF-1R, andfor pharmaceutical formulations and medicaments that contain suchcompounds. A need also exists for selective CSF-1R inhibitory compounds.A need also exists for methods of administering such compounds,pharmaceutical formulations, and medicaments to patients or subjects inneed thereof.

One embodiment is directed to compounds, stereoisomers, tautomers,solvates, oxides, esters, and prodrugs of Formula (I), thepharmaceutically acceptable salts thereof, and the related compositionsand methods wherein Formula (I) is:

and wherein X is O, S, or S(O);

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, heteroaryl, andsubstituted heteroaryl; or R¹ and R² are taken together to form a groupselected from heterocyclyl, substituted heterocyclyl, heteroaryl, orsubstituted heteroaryl;

R³ is selected from the group consisting of hydrogen, halo, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,carbonitrile, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl;

each R⁶ is independently alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, or halo;

n is 0, 1, or 2; and

when X is O, R⁴ is hydrogen, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, or substituted alkynyl, and R⁵ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aminocarbonyl, halo, heteroaryl, substituted heteroaryl,cycloalkyl, or substituted cycloalkyl, or R⁴ and R⁵ are taken togetherto form a group selected from heterocyclyl, substituted heterocyclyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; and

when X is S or S(O), R⁴ is hydrogen, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, or substituted alkynyl, and R⁵ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aminocarbonyl, halo, heteroaryl,substituted heteroaryl, cycloalkyl, or substituted cycloalkyl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IIa) or (IIb), the pharmaceutically acceptablesalts thereof, and the related compositions and methods wherein Formula(IIa) and (IIb) are

and wherein X is O or S;

the dashed lines are saturated bonds or unsaturated bonds;

L is a covalent bond or is alkylidene or substituted alkylidene;

R¹⁰, R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; or R¹¹ is taken together withR¹² to form a group selected from the group consisting of aryl,substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl,and substituted heteroaryl; and

R³ is selected from the group consisting of hydrogen, halogen,substituted alkyl, carbonitrile, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IIIa), the pharmaceutically acceptable saltsthereof, and the related compositions and methods wherein Formula (IIIa)is

and wherein X is O or S;

R¹ is alkyl or alkyl substituted with a substituent selected from thegroup consisting of aryl, cycloalkyl, heterocyclyl, substitutedheterocyclyl, heteroaryl, and substituted heteroaryl; and

R³ is selected from the group consisting of hydrogen, halogen,substituted alkyl, carbonitrile, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IIIb), the pharmaceutically acceptable saltsthereof, and the related compositions and methods wherein Formula (IIIb)is

and wherein X is O or S;

R¹ is selected from the group consisting of acyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclyl, substituted heterocyclyl, heteroaryl, and substitutedheteroaryl; and

R³ is selected from the group consisting of hydrogen, halogen,substituted alkyl, carbonitrile, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IV), the pharmaceutically acceptable saltsthereof, and the related compositions and methods wherein Formula (IV)is

and wherein X is O or S;

R⁷ is independently selected from the group consisting of alkoxy,haloalkoxy, halo, and carbonitrile;

p is 0, 1, or 2;

R¹ is -LR⁸ or alkyl substituted with 0, 1, 2, or 3 substituentsindependently selected from halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, aryloxy, aminocarbonyl, carboxyl ester, carboxy, andsubstituted sulfonyl;

L is a covalent bond, alkylidene, or substituted alkylidene; and

R⁸ is selected from the group consisting of cycloalkyl, substitutedcycloalkyl, tetrahydropyranyl, morpholino, pyridyl, and when p is 0, R⁸is optionally 2-methoxyphenyl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (V), the pharmaceutically acceptable saltsthereof, and the related compositions and methods wherein Formula (V) is

and wherein X is O or S;

R¹ is -LR⁹ or alkyl substituted with 0, 1, 2, or 3 substituentsindependently selected from halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, aryloxy, aminocarbonyl, carboxyl ester, carboxy, andsubstituted sulfonyl;

L is a covalent bond, alkylidene, or substituted alkylidene; and

R⁹ is selected from the group consisting of cycloalkyl, substitutedcycloalkyl, tetrahydropyranyl, morpholino, and pyridyl.

Another embodiment is directed to a method of treating a CSF-1R mediateddisorder with a CSR-1R inhibitory compound of Formula (I), (IIa), (IIb),(IIIa), (IIIb), (IV), or (V).

In a more particular embodiment said compound does not substantiallyinhibit Raf kinase. In a more particular embodiment said compoundpreferentially inhibits CSF-1R over Raf kinase. In a more particularembodiment said compound inhibits Raf kinase at an IC₅₀ of greater thanabout 1 μM. In a more particular embodiment said compound inhibitsCSF-1R at an IC₅₀ of at less than about 1 μM. More particular still,said compound inhibits CSF-1R at an IC₅₀ of at less than about 0.1 μM.

DETAILED DESCRIPTION

Throughout this application, the text refers to various embodiments ofthe present compounds, compositions, and methods. The variousembodiments described are meant to provide a variety illustrativeexamples and should not be construed as descriptions of alternativespecies. Rather it should be noted that the descriptions of variousembodiments provided herein may be of overlapping scope. The embodimentsdiscussed herein are merely illustrative and are not meant to limit thescope of the present invention.

DEFINITIONS

Unless specifically defined otherwise, the terms used herein are definedbelow.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Substituted alkyl” refers to an alkyl group having from 1 to 5,preferably 1 to 3, or more preferably 1 to 2 substituents selected fromthe group consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cyanate, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl,substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,heteroarylthio, substituted heteroarylthio, heterocyclic, substitutedheterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro,spirocycloalkylidene, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl,thiocyanate, thiol, alkylthio, and substituted alkylthio, wherein saidsubstituents are defined herein.

“Alkylidene” or “alkylene” refers to divalent saturated aliphatichydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to6 carbon atoms. The alkylidene and alkylene groups include branched andstraight chain hydrocarbyl groups.

“Substituted alkylidene” or “substituted alkylene” refers to analkylidene group having from 1 to 5, preferably 1 to 3, or morepreferably 1 to 2 substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substitutedamino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cyanate, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substitutedcycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio,guanidino, substituted guanidino, halo, hydroxy, hydroxyamino,alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, oxo, thione, spirocycloalkylidene,SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein.

“Alkoxy” refers to the group —O-alkyl wherein alkyl is defined herein.Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

“Substituted alkoxy” refers to the group —O-(substituted alkyl) whereinsubstituted alkyl is defined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, substituted hydrazino-C(O)—,heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, andsubstituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, substituted hydrazino, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein. Acyl includes the “acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, —NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic wherein R²⁰is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, cycloalkenyl-C(O)O—, substitutedcycloalkenyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O— wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR²¹R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cylcoalkyl, —SO₂-cycloalkenyl,—SO₂-substituted cycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl,—SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, and—SO₂-substituted heterocyclic and wherein R²¹ and R²² are optionallyjoined, together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that R²¹ and R²² are bothnot hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl are as defined herein. When R²¹ is hydrogen and R²² isalkyl, the substituted amino group is sometimes referred to herein asalkylamino. When R²¹ and R²² are alkyl, the substituted amino group issometimes referred to herein as dialkylamino. When referring to amonosubstituted amino, it is meant that either R²¹ or R²² is hydrogenbut not both. When referring to a disubstituted amino, it is meant thatneither R²¹ nor R²² are hydrogen.

“Hydroxyamino” refers to the group —NHOH.

“Alkoxyamino” refers to the group —NHO-alkyl wherein alkyl is definedherein.

“Aminocarbonyl” refers to the group —C(O)NR²³R²⁴ where R²³ and R²⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl, hydroxy, alkoxy,substituted alkoxy, amino, substituted amino, and acylamino, and whereR²³ and R²⁴ are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonyl” refers to the group —C(S)NR²³R²⁴ where R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminocarbonylamino” refers to the group —NR²⁰C(O)NR²³R²⁴ where R²⁰ ishydrogen or alkyl and R²³ and R²⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl and where R²³ and R²⁴ are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR²⁰C(S)NR²³R²⁴ where R²⁰is hydrogen or alkyl and R²³ and R²⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl and where R²³ and R²⁴ are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR²³R²⁴ where R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonyl” refers to the group —SO₂NR²³R²⁴ where R²³ and R²⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR²³R²⁴ where R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonylamino” refers to the group —NR²⁰—SO₂NR²³R²⁴ where R²⁰ ishydrogen or alkyl and R²³ and R²⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl and where R²³ and R²⁴ are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkyenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Amidino” refers to the group —C(═NR²⁵)NR²³R²⁴ where R²⁵, R²³, and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the pointof attachment is at an aromatic carbon atom. Preferred aryl groupsinclude phenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with 1 to5, preferably 1 to 3, or more preferably 1 to 2 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cyanate, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substitutedcycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio,guanidino, substituted guanidino, halo, hydroxy, hydroxyamino,alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, and substitutedalkylthio, wherein said substituents are defined herein.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein,that includes, by way of example, phenoxy and naphthoxy.

“Substituted aryloxy” refers to the group —O-(substituted aryl) wheresubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, where aryl is as defined herein.

“Substituted arylthio” refers to the group —S-(substituted aryl), wheresubstituted aryl is as defined herein.

“Alkenyl” refers to alkenyl groups having from 2 to 6 carbon atoms andpreferably 2 to 4 carbon atoms and having at least 1 and preferably from1 to 2 sites of vinyl unsaturation (>C═C<). Such groups are exemplified,for example, by vinyl, allyl, and but-3-en-yl.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substitutedcycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein and with the proviso thatany hydroxy or thiol substitution is not attached to a vinyl(unsaturated) carbon atom.

“Alkynyl” refers to hydrocarbyl groups having from 2 to 6 carbon atomsand preferably 2 to 3 carbon atoms and having at least 1 and preferablyfrom 1 to 2 sites of acetylenic unsaturation (—C≡C—).

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substitutedcycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein and with the proviso thatany hydroxy or thiol substitution is not attached to an acetyleniccarbon atom.

“Azido” refers to the group —N₃.

“Hydrazino” refers to the group —NHNH₂.

“Substituted hydrazino” refers to the group —NR²⁶NR²⁷R²⁸ where R²⁶, R²⁷,and R²⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, carboxyl ester,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cylcoalkyl, —SO₂-cycloalkenyl, —SO₂-substitutedcycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic and wherein R²⁷ and R²⁸ are optionally joined, togetherwith the nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, provided that R²⁷ and R²⁸ are both not hydrogen, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl areas defined herein.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cyanate” refers to the group —OCN.

“Carbonyl” refers to the divalent group —C(O)— which is equivalent to—C(═O)—.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic,and —C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl are as defined herein.

“(Carboxyl ester)amino” refers to the group —NR²⁰—C(O)O-alkyl,—NR²⁰—C(O)O-substituted alkyl, —NR²⁰—C(O)O-alkenyl,—NR²⁰—C(O)O-substituted alkenyl, —NR²⁰—C(O)O-alkynyl,—NR²⁰—C(O)O-substituted alkynyl, —NR²⁰—C(O)O-aryl,—NR²⁰—C(O)O-substituted aryl, —NR²⁰—C(O)O-cycloalkyl,—NR²⁰—C(O)O-substituted cycloalkyl, —NR²⁰—C(O)O-cycloalkenyl,—NR²⁰—C(O)O-substituted cycloalkenyl, —NR²⁰—C(O)O-heteroaryl,—NR²⁰—C(O)O-substituted heteroaryl, —NR²⁰—C(O)O-heterocyclic, and—NR²⁰—C(O)O-substituted heterocyclic wherein R²⁰ is alkyl or hydrogen,and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl are as defined herein.

“(Carboxyl ester)oxy” refers to the group —O—C(O)O-alkyl,—O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl,—O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl areas defined herein.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. In fused ring systems, one or more the rings can becycloalkyl, heterocyclic, aryl, or heteroaryl provided that the point ofattachment is through the cycloalkyl ring. Examples of suitablecycloalkyl groups include, for instance, adamantyl, cyclopropyl,cyclobutyl, cyclopentyl, and cyclooctyl.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 4 to10 carbon atoms having single or multiple cyclic rings and having atleast one >C═C< ring unsaturation and preferably from 1 to 2 sitesof >C═C< ring unsaturation.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to acycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3substituents selected from the group consisting of oxo, thione, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cyanate, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substitutedcycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio,guanidino, substituted guanidino, halo, hydroxy, hydroxyamino,alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, and substitutedalkylthio, wherein said substituents are defined herein.

“Cycloalkyloxy” refers to —O-cycloalkyl.

“Substituted cycloalkyloxy refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl).

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl).

“Cycloalkenylthio” refers to —S-cycloalkenyl.

“Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl).

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to —NR²⁹C(═NR²⁹)N(R²⁹)₂ where each R²⁹ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and two R²⁹groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R²⁹ is nothydrogen, and wherein said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to substitution of alkyl groups with 1 to 5 orpreferably 1 to 3 halo groups.

“Haloalkoxy” refers to substitution of alkoxy groups with 1 to 5 orpreferably 1 to 3 halo groups.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl) wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom provided that the pointof attachment is through an atom of the aromatic heteroaryl group. Inone embodiment, the nitrogen and/or the sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls includepyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to2 substituents selected from the group consisting of the same group ofsubstituents defined for substituted aryl.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl).

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated, partially saturated, or unsaturated group (butnot aromatic) having a single ring or multiple condensed rings,including fused bridged and spirocycyl ring systems, from 1 to 10 carbonatoms and from 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more the rings can be cycloalkyl, aryl or heteroarylprovided that the point of attachment is through the non-aromatic ring.In one embodiment, the nitrogen and/or sulfur atom(s) of theheterocyclic group are optionally oxidized to provide for the N-oxide,sulfinyl, sulfonyl moieties.

“Substituted heterocyclic” or “substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that aresubstituted with from 1 to 5 or preferably 1 to 3 of the samesubstituents as defined for substituted cycloalkyl.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl).

Examples of heterocycle and heteroaryls include, but are not limited to,azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indolizine, isoindole, indole, dihydroindole, indazole,purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,and tetrahydrofuranyl.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Oxide” refers to products resulting from the oxidation of one or moreheteroatoms. Examples include N-oxides, sulfoxides, and sulfones.

“Spirocyclyl” refers to divalent cyclic groups from 3 to 10 carbon atomshaving a cycloalkyl or heterocyclyl ring with a spiro union (the unionformed by a single atom which is the only common member of the rings) asexemplified by the following structure:

“Spirocycloalkyl” or “spirocycloalkylidene” refers to divalent cyclicgroups having a cycloalkyl ring with a spiro union, as described forspirocyclyl.

“Sulfonyl” refers to the divalent group —S(O)₂—.

“Substituted sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substitutedalkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cylcoalkyl, —SO₂-cycloalkenyl, —SO₂-substitutedcycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, —SO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein. Substituted sulfonyl includes groupssuch as methyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cylcoalkyl, —OSO₂-cycloalkenyl, —OSO₂-substitutedcycloalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, —OSO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—,aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substitutedheteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Alkylthio” refers to the group —S-alkyl wherein alkyl is as definedherein.

“Substituted alkylthio” refers to the group —S-(substituted alkyl)wherein substituted alkyl is as defined herein.

“Thiocarbonyl” refers to the divalent group —C(S)— which is equivalentto —C(═S)—.

“Thione” refers to the atom (═S).

“Thiocyanate” refers to the group —SCN.

“Solvate” or “solvates” refer compounds or a salt thereof that are boundto a stoichiometric or non-stoichiometric amount of a solvent. Preferredsolvents are volatile, non-toxic, and/or acceptable for administrationto humans in trace amounts. Suitable solvates include water.

“Stereoisomer” or “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers.

“Tautomer” refer to alternate forms of a compound that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— moiety and a ring ═N— moeity such aspyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

“Prodrug” refers to any derivative of a compound of the embodiments thatis capable of directly or indirectly providing a compound of theembodiments or an active metabolite or residue thereof when administeredto a subject. Particularly favored derivatives and prodrugs are thosethat increase the bioavailability of the compounds of the embodimentswhen such compounds are administered to a subject (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies. Prodrugs include ester forms of the compounds of the invention.Examples of ester prodrugs include formate, acetate, propionate,butyrate, acrylate, and ethylsuccinate derivatives. An general overviewof prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in EdwardB. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound, which salts are derived from a variety of organicand inorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium, andtetraalkylammonium; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, andoxalate. The term also includes pharmaceutically acceptable salts ofstereoisomers, tautomers, esters, and prodrugs of the compound.

“Patient” refers to mammals and includes humans and non-human mammals.

“Treating” or “treatment” of a disease in a patient refers to 1)preventing the disease from occurring in a patient that is predisposedor does not yet display symptoms of the disease; 2) inhibiting thedisease or arresting its development; or 3) ameliorating or causingregression of the disease.

Reference to “selective” inhibition, refers to a compound, composition,or chemotype that preferentially inhibits a particular target or classof targets. Reference to “selective inhibition of CSF-1R” indicates thepreferential inhibition of CSF-1R and optionally like kinase receptorssuch as PDGFR. In some embodiments, selective inhibition of CSF-1Rrefers to preferential inhibition of CSF-1R over Raf kinase.“Selective,” “targeted,” “specific,” or “preferential” inhibition is notintended to mean complete absence of inhibitory activity with respect toall other kinases or receptors.

“CSF-1R inhibitor” refers to a compound that can inhibit CSF-1R.Preferably, a CSF-1R inhibitor is selective of CSF-1R over othertargets. In an embodiment, a CSF-1R inhibitor has selective inhibitionof CSF-1R over Raf kinase. In a preferred embodiment, such selectiveinhibition refers to at least a 2:1 binding preference of a compound ofthis invention to CSF-1R relative to Raf kinase, more preferably atleast 5:1, and even more preferably at least 10:1.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups with two other substituted aryl groups are limited to-substituted aryl-(substituted aryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns are wellknown to the skilled artisan.

One embodiment is directed to compounds, stereoisomers, tautomers,solvates, oxides, esters, and prodrugs of Formula (I), thepharmaceutically acceptable salts thereof, and the related compositionsand methods wherein Formula (I) is:

and wherein X is O, S, or S(O);

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, heteroaryl, andsubstituted heteroaryl; or R¹ and R² are taken together to form a groupselected from heterocyclyl, substituted heterocyclyl, heteroaryl, orsubstituted heteroaryl;

R³ is selected from the group consisting of hydrogen, halo, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,carbonitrile, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl;

each R⁶ is independently alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, or halo;

n is 0, 1, or 2; and

when X is O, R⁴ is hydrogen, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, or substituted alkynyl, and R⁵ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aminocarbonyl, halo, heteroaryl, substituted heteroaryl,cycloalkyl, or substituted cycloalkyl, or R⁴ and R⁵ are taken togetherto form a group selected from heterocyclyl, substituted heterocyclyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; and

when X is S or S(O), R⁴ is hydrogen, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, or substituted alkynyl, and R⁵ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aminocarbonyl, halo, heteroaryl,substituted heteroaryl, cycloalkyl, or substituted cycloalkyl.

In some embodiments, X is O.

In some embodiments, X is S.

In some embodiments, X is S(O).

In some embodiments, the oxide of Formula (I) is an oxide wherein X isS(O)₂.

In some embodiments, R² is hydrogen or methyl.

In some embodiments, R¹ is alkyl substituted with 0, 1, 2, or 3substituents independently selected from halo, hydroxy, haloalkyl,alkoxy, haloalkoxy, aryloxy, aminocarbonyl, carboxyl ester, carboxyl,and substituted sulfonyl. Substituted and unsubstituted R¹ alkyl groupsinclude branched hydrocarbyl groups such as pent-2-yl.

In some embodiments, R¹ is -LR^(1a) wherein L is a covalent bond,alkylidene, or substituted alkylidene, and R^(1a) selected fromcycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl, whereineach R^(1a) is substituted or unsubstituted.

In some aspects, R^(1a) is selected from phenyl, furan-2-yl, furan-3-yl,tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclohexenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine,3,4-dihydro-2H-benzo[b][1,4]dioxepine, pyrazinyl, pyrrolidinyl,piperidinyl, piperidinone, pyrrolidinone, pyridin-2(1H)-one, morpholino,napthyl, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, and azepan-2-one,wherein each R^(1a) is substituted or unsubstituted. In some suchaspects L is a covalent bond.

In some embodiments, L is a covalent bond.

In some embodiments of the compound of Formula (I), L is alkylidenesubstituted with 0, 1, 2, or 3 substituents independently selected fromalkyl, substituted alkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyl,carboxyl ester, and carboxyl.

In some embodiments of the compound of Formula (I), R¹ is

wherein the dashed lines are saturated bonds or unsaturated bonds;

wherein L is a covalent bond or is alkylidene or substituted alkylidene;and

R¹⁰, R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; or R¹¹ is taken together withR¹² to form a group selected from the group consisting of aryl,substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl,and substituted heteroaryl. In some aspects, R¹⁰ is hydrogen.

In some embodiments, the dashed lines are saturated bonds, therebyforming a cyclohexyl group.

In some embodiments of the compound of Formula (I), L is a covalentbond.

In some embodiments of the compound of Formula (I), L is methylene orsubstituted methylene.

In some embodiments of the compound of Formula (I) when L is not acovalent bond, L is substituted with alkyl, substituted alkyl, carboxyl,aminocarbonyl, and carboxyl ester.

In some embodiments of the compound of Formula (I), R¹⁰, R¹¹, and R¹²are independently selected from the group consisting of hydrogen, halo,hydroxyl, alkyl, substituted alkyl, and alkoxy.

In some embodiments of the compound of Formula (I), at least one of R¹⁰,R¹¹, and R¹² is hydroxyl.

In some embodiments, R¹¹ and R¹² are independently selected from thegroup consisting of hydrogen, halo, alkyl, substituted alkyl, andalkoxy.

In some embodiments, R¹¹ is taken together with R¹² to form aryl orsubstituted aryl.

In some embodiments, R¹ is alkyl or substituted alkyl.

In some embodiments, R¹ is substituted alkyl, wherein the substituent ofR¹ is selected from the group consisting of alkyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, heteroaryl, and substituted heteroaryl.

In some embodiments, R¹ is substituted alkyl, wherein the substituent ofR¹ is selected from the group consisting of alkyl, aryl, cycloalkyl,heterocyclyl, substituted heterocyclyl, heteroaryl, and substitutedheteroaryl.

In some embodiments, R¹ is substituted alkyl, wherein the substituent ofR¹ is cycloalkyl or substituted cycloalkyl.

In some embodiments, R¹ is substituted alkyl, wherein the substituent ofR¹ is cycloalkyl or substituted cycloalkyl.

In some embodiments, R¹ is selected from the group consisting ofcycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclyl, substituted heterocyclyl, heteroaryl, andsubstituted heteroaryl.

In some embodiments, R¹ is selected from the group consisting ofcycloalkyl, substituted cycloalkyl, heterocyclyl, and substitutedheterocyclyl.

In some embodiments, R³ is acylamino or aminocarbonyl.

In some embodiments, R³ is —C(O)NH-LR^(3a) wherein L is a covalent bond,alkylidene, or substituted alkylidene, and R^(3a) is selected from thegroup consisting of alkyl, haloalkyl, amino, acylamino, (carboxylester)amino, hydroxy, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

In some embodiments, R³ is —C(O)NHCH₃.

In some embodiments, R³ is hydrogen, carboxyl, substituted alkyl,carbonitrile, heteroaryl, or substituted heteroaryl.

In some embodiments, R³ is selected from the group consisting ofpyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridine-2-yl, pyridine-3-yl,pyridine-4-yl, pyrimidin-4-yl, pyrimidin-3-yl, pyrimidin-2-yl, thiazoyl,tetrazolyl, imidazol-1-yl, imidazol-2-yl, imidazol-3-yl, pyrazinyl,phenyl, tetrahydropyridine, 1H-pyrrolo[2,3-b]pyridine, furanyl, oxazole,oxadiazole, cyclopropyl, cyclohexyl, cyclohexenyl, piperidinyl,morpholino, tetrahydro-1H-benzo[d]imidazole, pyrrolidinyl, piperazinyl,and piperazin-2-one, wherein each R³ is substituted or unsubstituted.

In some embodiments, R⁴ is hydrogen.

In some embodiments, R⁵ is hydrogen.

In some embodiments and in combination with any of the aforementionedembodiments, n is 0, R⁴ and R⁵ are hydrogen, and R³ is selected from thegroup consisting of hydrogen, halo, substituted alkyl, carbonitrile,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, substituted heterocyclyl, amino, substituted amino, acyl,acylamino, alkoxy, substituted alkoxy, carboxyl, carboxyl ester,substituted sulfonyl, aminosulfonyl, and aminocarbonyl.

In some embodiments, R⁴ and R⁵ are taken together to form an aryl orsubstituted aryl group.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IIa) or (IIb), the pharmaceutically acceptablesalts thereof, and the related compositions and methods

wherein X is O or S;

wherein the dashed lines are saturated bonds or unsaturated bonds;

wherein L is a covalent bond or is alkylidene or substituted alkylidene;

R¹⁰, R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; or R¹¹ is taken together withR¹² to form a group selected from the group consisting of aryl,substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl,and substituted heteroaryl; and

R³ is selected from the group consisting of hydrogen, halogen,substituted alkyl, carbonitrile, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl.

In some embodiments of the compound of Formula (IIa) or (IIb), X is O.

In some embodiments of the compound of Formula (IIa) or (IIb), X is S.

In some embodiments, the dashed lines are saturated bonds, therebyforming a cyclohexyl group.

In some embodiments of the compound of Formula (IIa) or (IIb), L is acovalent bond.

In some embodiments of the compound of Formula (IIa) or (IIb), L ismethylene or substituted methylene.

In some embodiments of the compound of Formula (IIa) or (IIb), L issubstituted with alkyl, substituted alkyl, carboxyl, aminocarbonyl, orcarboxyl ester.

In some embodiments of the compound of Formula (IIa) or (IIb), R¹⁰, R¹¹,and R¹² are independently selected from the group consisting ofhydrogen, halo, hydroxyl, alkyl, substituted alkyl, and alkoxy.

In some embodiments of the compound of Formula (IIa) or (IIb), at leastone of R¹⁰, R¹¹, and R¹² is hydroxyl.

In some embodiments of the compound of Formula (IIa) or (IIb), R¹¹ andR¹² are independently selected from the group consisting of hydrogen,halo, alkyl, substituted alkyl, and alkoxy.

In some embodiments of the compound of Formula (IIa) or (IIb), R¹¹ istaken together with R¹² to form aryl or substituted aryl.

In some embodiments of the compound of Formula (IIa) or (IIb), R³ isacylamino or aminocarbonyl.

In some embodiments of the compound of Formula (IIa) or (IIb), R³ is—C(O)NHCH₃.

In some embodiments of the compound of Formula (IIa) or (IIb), R³ ishydrogen, carboxyl, substituted alkyl, carbonitrile, heteroaryl, orsubstituted heteroaryl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IIIa), the pharmaceutically acceptable saltsthereof, and the related compositions and methods wherein Formula (IIIa)is

and wherein X is O or S;

R¹ is alkyl or alkyl substituted with a substituent selected from thegroup consisting of aryl, cycloalkyl, heterocyclyl, substitutedheterocyclyl, heteroaryl, and substituted heteroaryl; and

R³ is selected from the group consisting of hydrogen, halogen,substituted alkyl, carbonitrile, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl.

In some embodiments of the compound of Formula (IIa), X is O.

In some embodiments of the compound of Formula (IIa), X is S.

In some embodiments of the compound of Formula (IIa), R¹ is alkylsubstituted with cycloalkyl.

In some embodiments of the compound of Formula (IIa), R³ is acylamino oraminocarbonyl.

In some embodiments of the compound of Formula (IIa), R³ is —C(O)NHCH₃.

In some embodiments of the compound of Formula (IIa), R³ is hydrogen,carboxyl, substituted alkyl, carbonitrile, heteroaryl, or substitutedheteroaryl.

Another embodiment is directed to compounds, stereoisomers, tautomers,and solvates of Formula (IIIb), the pharmaceutically acceptable saltsthereof, and the related compositions and methods wherein Formula (IIIb)is

and wherein X is O or S;

R¹ is selected from the group consisting of acyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclyl, substituted heterocyclyl, heteroaryl, and substitutedheteroaryl; and

R³ is selected from the group consisting of hydrogen, halogen,substituted alkyl, carbonitrile, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, amino,substituted amino, acyl, acylamino, alkoxy, substituted alkoxy,carboxyl, carboxyl ester, substituted sulfonyl, aminosulfonyl, andaminocarbonyl.

In some embodiments of the compound of Formula (IIIb), X is O.

In some embodiments of the compound of Formula (IIIb), X is S.

In some embodiments of the compound of Formula (IIIb), R¹ is selectedfrom the group consisting of cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl.

In some embodiments of the compound of Formula (IIIb), R³ is acylaminoor aminocarbonyl.

In some embodiments of the compound of Formula (IIIb), R³ is —C(O)NHCH₃.

In some embodiments of the compound of Formula (IIIb), R³ is hydrogen,carboxyl, substituted alkyl, carbonitrile, heteroaryl, or substitutedheteroaryl.

In some embodiments of the compound of Formula (IIIb), R³ is—C(O)NH-LR^(3a), wherein L is a covalent bond, alkylidene, orsubstituted alkylidene, and R^(3a) is selected from the group consistingof alkyl, haloalkyl, amino, acylamino, (carboxyl ester)amino, hydroxy,alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl.

In some embodiments of the compound of Formula (IIIb), R³ is selectedfrom the group consisting of pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl,pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidin-4-yl,pyrimidin-3-yl, pyrimidin-2-yl, thiazoyl, tetrazolyl, imidazol-1-yl,imidazol-2-yl, imidazol-3-yl, pyrazinyl, phenyl, tetrahydropyridine,1H-pyrrolo[2,3-b]pyridine, furanyl, oxazole, oxadiazole, cyclopropyl,cyclohexyl, cyclohexenyl, piperidinyl, morpholino,tetrahydro-1H-benzo[d]imidazole, pyrrolidinyl, piperazinyl, andpiperazin-2-one, wherein each R³ is substituted or unsubstituted.

Another embodiment is directed to a compound, stereoisomer, tautomer,solvate, oxide, ester, and prodrug of Formula (IV), a pharmaceuticallyacceptable salt thereof, and the related compositions and methodswherein Formula (IV) is

and wherein X is O or S;

R⁷ is independently selected from the group consisting of alkoxy,haloalkoxy, halo, and carbonitrile;

p is 0, 1, or 2;

R¹ is -LR⁸ or alkyl substituted with 0, 1, 2, or 3 substituentsindependently selected from halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, aryloxy, aminocarbonyl, carboxyl ester, carboxy, andsubstituted sulfonyl;

L is a covalent bond, alkylidene, or substituted alkylidene; and

R⁸ is selected from the group consisting of cycloalkyl, substitutedcycloalkyl, tetrahydropyranyl, morpholino, pyridyl, and when p is 0,R^(1a) is optionally 2-methoxyphenyl.

In some embodiments, X is S.

In some embodiments, p is 0.

Another embodiment is directed to a compound, stereoisomer, tautomer,solvate, oxide, ester, and prodrug of Formula (V), the pharmaceuticallyacceptable salt thereof, and the related compositions and methodswherein Formula (V) is

wherein X is O or S;

R¹ is -LR⁹ or alkyl substituted with 0, 1, 2, or 3 substituentsindependently selected from halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, aryloxy, aminocarbonyl, carboxyl ester, carboxy, andsubstituted sulfonyl;

L is a covalent bond, alkylidene, or substituted alkylidene; and

R⁹ is selected from the group consisting of cycloalkyl, substitutedcycloalkyl, tetrahydropyranyl, morpholino, and pyridyl.

In some embodiments, X is S.

In some embodiments, L is a covalent bond or is alkylidene.

In some embodiments, R⁹ is cyclohexyl or substituted cyclohexyl.

Representative compounds are presented in Table 1.

TABLE 1

Cmpd. No. X R¹ R² R⁴ R⁵ R³ 1 O 4-bromophenyl H H H —C(O)NHCH₃ 2 O2-(R)-1-phenylethyl H H H —C(O)NHCH₃ 3 O 2-morpholin-4-ylphenyl H H H—C(O)NHCH₃ 4 O 2,3-dihydrobenzo[1,4]- dioxin-6-yl H

H 5 O (2,3- H H H —C(O)NHCH₃ dihydrobenzo[1,4]dioxin-6-yl 6 O(1-thiazol-2-yl-ethyl) H H H —C(O)NHCH₃ 7 O 2-(S)-phenylethyl H H H—C(O)NHCH₃ 8 O 2-chlorobenzyl H H H —C(O)NHCH₃ 9 O 2,4-dichlorobenzyl HH H —C(O)NHCH₃ 10 O 3-methylcyclohexyl H H H —C(O)NHCH₃ 11 O2-methoxyphenyl H H H —C(O)NHCH₃ 12 O 2-ethoxyphenyl H H H —C(O)NHCH₃ 13O (1S,2S,3S,5R)-2,6,6- H H H —C(O)NHCH₃ trimethylbicyclo-[3.1.1]hept-3-yl 14 O 1-(R)-phenylethyl H

H 15 O (1S,2R,4R)-7,7- H H H —C(O)NHCH₃ dimethylbicyclo-[2.1.1]hept-2-ylmethyl 16 O 2-fluorobenzyl H H H —C(O)NHCH₃ 17 O2-methoxybenzyl H H H —C(O)NHCH₃ 18 O 2-(R)-1-naphthalenylethyl H H H—C(O)NHCH₃ 19 O 2-(R)-1-phenylpropyl H H H —C(O)NHCH₃ 20 O2-(S)-1-naphthalen-2-ylethyl H H H —C(O)NHCH₃ 21 O cyclohexylmethyl H HH —C(O)NHCH₃ 22 O cyclobutyl H H H —C(O)NHCH₃ 23 O cyclopentyl H H H—C(O)NHCH₃ 24 O cyclohexyl H H H —C(O)NHCH₃ 25 O(2-morpholin-4-ylmethyl) H H H —C(O)NHCH₃ 26 O phenyl H H H —C(O)NHCH₃27 O (4-chlorobenzyl) H H H —C(O)NHCH₃ 28 O 2,4-dimethoxyphenyl H H H—C(O)NHCH₃ 29 O cyclohexyl H H H —NHC(O)CH₃ 30 O tetrahydropyran-4-yl HH H —C(O)NHCH₃ 31 O 2-(R)-1-(2-methoxyphenyl) H H H —C(O)NHCH₃ 32 O2-chlorobenzyl H H H —C(O)NHCH₃ 33 O 2,5-difluorobenzyl H H H —NHC(O)CH₃34 O cyclohexylmethyl H H H —NHC(O)CH₃ 35 O 2-(R)-phenylacetic acid H HH —C(O)NHCH₃ 36 O 2-(R)-carboxylic acid H H H —C(O)NHCH₃ methylamide 37O 2-(R)-hydroxy-1-phenyl- H H H —C(O)NHCH₃ ethyl 38 O 2-(S)-phenylaceticacid H H H —C(O)NHCH₃ 39 O 2-(S)-carboxylic acid H H H —C(O)NHCH₃methylamide 40 O Pyridine-2-ylmethyl H H H —C(O)NHCH₃ 41 O benzyl H H H—C(O)NHCH₃ 42 O 3-chlorobenzyl H H H —C(O)NHCH₃ 43 O 2-(2-pyrrolidin-1-H H H —C(O)NHCH₃ ylethyl)phenyl 44 O 2-(2-piperidin-1- H H H —C(O)NHCH₃ylethyl)phenyl 45 O 2-(4-methyl-imidazol-1- H H H —C(O)NHCH₃ yl)phenyl46 O 2-oxazol-5-ylphenyl H H H —C(O)NHCH₃ 47 O 2-(2-methylimidazol-1- HH H —C(O)NHCH₃ yl)phenyl 48 O 2-morpholin-4-yl-ethyl H H H —C(O)NHCH₃ 49O (1S,2R)-2-hydroxy-indan-1-yl H H H —C(O)NHCH₃ 50 O(1R,2S)-2-hydroxy-indan-1-yl H H H —C(O)NHCH₃ 51 O 2-(R)-3-hydroxy-1- HH H —C(O)NHCH₃ phenylpropyl 52 O (1S,2S)-2-hydroxycyclohexyl H H H—C(O)NHCH₃ 53 O 2-(R)-phenylacetic acid H H H —C(O)NHCH₃ methyl ester 54O 2-(R)-cyclohexylethyl H H H —C(O)NHCH₃ 55 O 2-(S)-phenylacetic acid HH H —C(O)NHCH₃ methyl ester 56 O 2-(S)-hydroxy-1-phenylethyl H H H—C(O)NHCH₃ 57 O Pyridine-4-ylmethyl H H H —C(O)NHCH₃ 58 O2-piperidin-1-ylethyl H H H —C(O)NHCH₃ 59 O Pyrindin-3-ylmethyl H H H—C(O)NHCH₃ 60 O cyclohexylmethyl H H H —C(O)OH 61 O phenethyl H H H—C(O)NHCH₃ 62 O 2-(R)-cyclohexylmethyl- H H H —C(O)NHCH₃ carbamoylmethyl63 O 2-pyrrolidin-1-ylethyl H H H —C(O)NHCH₃ 64 O 2-piperidin-1-ylethylH H H —C(O)NHCH₃ 65 O 2,3-dihydrobenzo- H H H —C(O)NHCH₃[1,4]dioxin-5-ylmethyl 66 O 2-(S)-1-cyclohexyl-2- H H H —C(O)NHCH₃hydroxyethyl 67 O 2-(R)-1-cyclohexyl-2- H H H —C(O)NHCH₃ hydroxyethyl 68O cyclohexylmethyl H H H —C(O)NHNHC(O)OC(CH₃)₃ 69 O cyclohexylmethyl H HH —C(O)NH₂ 70 O Cyclohex-3-enyl H H H —C(O)NHCH₃ 71 O 2,4-difluorobenzylH H H —C(O)NHCH₃ 72 O 2-bromobenzyl H H H —C(O)NHCH₃ 73 O2-fluoro-5-methoxybenzyl H H H —C(O)NHCH₃ 74 O 3-(2-morpholin-4- H H H—C(O)NHCH₃ ylethyl)phenyl 75 O Cyclohexanecarboxylic acid H H H—C(O)NHCH₃ ethyl ester 76 O 2,6-dichlorobenzyl H H H —C(O)NHCH₃ 77 O2,3-dichlorobenzyl H H H —C(O)NHCH₃ 78 O 2-chloro-6-fluorobenzyl H H H—C(O)NHCH₃ 79 O 2,3,-difluorobenzyl H H H —C(O)NHCH₃ 80 Ocyclohexylmethyl H H H —CH₂OH 81 O cyclohexylmethyl H H H oxadiazolyl 82O cyclohexylmethyl H H H —CN 83 O 2,5-dimethoxybenzyl H H H —C(O)NHCH₃84 O 2,6-dimethoxybenzyl H H H —C(O)NHCH₃ 85 O 2-dimethyaminobenzyl H HH —C(O)NHCH₃ 86 O 2-aminobenzyl H H H —C(O)NHCH₃ 87 O 2,6-difluorobenzylH H H —C(O)NHCH₃ 88 O 2-morpholin-4-ylbenzyl H H H —C(O)NHCH₃ 89 O2-methylbenzyl H H H —C(O)NHCH₃ 90 O 3,4-dimethoxybenzyl H H H—C(O)NHCH₃ 91 O 2,3-dimethoxybenzyl H H H —C(O)NHCH₃ 92 O2,4-dimethoxybenzyl H H H —C(O)NHCH₃ 93 O Cyclohexanecarboxylic acid- HH H —C(O)NHCH₃ methyl 94 O 2,3-dihydrobenzo- H H H —C(O)NHCH₃[1,4]dioxin-5-yl 95 O Benzo[1,3]dioxol-5-yl H H H —C(O)NHCH₃ 96 O2-ethoxybenzyl H H H —C(O)NHCH₃ 97 O 2-trifluoromethylbenzyl H H H—C(O)NHCH₃ 98 O isopropyl H H H —C(O)NHCH₃ 99 O isobutyl H H H—C(O)NHCH₃ 100 O Tert-butyl H H H —C(O)NHCH₃ 101 O cycloheptylmethyl H HH —C(O)NHCH₃ 102 O Tetrahydrofuran-2-ylmethyl H H H —C(O)NHCH₃ 103 OBenzyl-piperidin-4-yl H H H —C(O)NHCH₃ 104 O1,2,3,4-tetrahydronaphthalen- H H H —C(O)NHCH₃ 1-yl 105 O2-pyrazol-1-ylbenzyl H H H —C(O)NHCH₃ 106 O benzyl CH₃ H H —C(O)NHCH₃107 O 1-phenyl-piperidin-4-yl H H H —C(O)NHCH₃ 108 O3,4-dihydro-2H-benzo- H H H —C(O)NHCH₃ [b][1,4]dioxepin-6ylmethyl 109 Ocyclohexylmethyl H H H 5-methyl-1H- imidazol-2-yl 110 O2,3-dihydrobenzo- H H H —C(O)NHCH₃ [1,4]dioxine-5-carbonyl 111 Ocyclohexylmethyl H H H —CH₂NH₂ 112 O Carboxylic acid methylamide H H H—C(O)NHCH₃ 113 O 2,4,6-trimethoxybenzyl H H H —C(O)NHCH₃ 114 O5-chloro-2-methoxybenzyl H H H —C(O)NHCH₃ 115 O 5-fluoro-2-methoxybenzylH H H —C(O)NHCH₃ 116 O 2-fluoro-6-methoxybenzyl H H H —C(O)NHCH₃ 117 O2-chloro-3,4- H H H —C(O)NHCH₃ dimethoxybenzyl 118 O2-piperidin-1-ylbenzyl H H H —C(O)NHCH₃ 119 O 2,3-dihydro-benzo- H H H—C(O)NHCH₃ [1,4]dioxin-2-ylmethyl 120 O 4-benzyl-morpholin-2- H H H—C(O)NHCH₃ ylmethyl 121 O 2-chloro-6-methoxybenzyl H H H —C(O)NHCH₃ 122O 2,3-dihydrobenzo- H H H —C(O)NHCH₃ [1,4]dioxin-6-ylmethyl 123 O2-(2,3-dihydrobenzo- H H H —C(O)NHCH₃ [1,4]dioxin-5-yl)ethyl 124 O2,3-dihydrobenzofuran-5- H H H —C(O)NHCH₃ ylmethyl 125 O2-(2,3-dihydrobenzo- H H H —C(O)NHCH₃ [1,4]dioxin-5-yl)ethyl 126 S4-chloro-3- H H H —C(O)NHCH₃ trifluoromethylphenyl 127 S 2-chlorobenzylH H H —C(O)NHCH₃ 128 S cyclohexylmethyl H H H —C(O)NHCH₃ 129 S2-(R)-1-(2- H H H —C(O)NHCH₃ methoxyphenyl)ethyl 130 S2,4-dichlorobenzyl H H H —C(O)NHCH₃ 131 S 2-(R)-1-phenylethyl H H H—C(O)NHCH₃ 132 S 2-methoxylbenzyl H H H —C(O)NHCH₃ 133 S 2-phenethyl H HH —C(O)NHCH₃ 134 S 2,3-dichlorobenzyl H H H —C(O)NHCH₃ 135 S cyclohexylH H H —C(O)NHCH₃ 136 S 3-methylcyclohexyl H H H —C(O)NHCH₃ 137 S(1S,2S)-2-hydroxycyclohexyl H H H —C(O)NHCH₃ 138 S 2-(R)-cyclohexylethylH H H —C(O)NHCH₃ 139 S 2,5-difluorobenzyl H H H —C(O)NHCH₃ 140 S2-fluorobenzyl H H H —C(O)NHCH₃ 141 S Tetrahydropyran-4-ylmethyl H H H—C(O)NHCH₃ 142 S 2-morpholin-4-ylbenzyl H H H —C(O)NHCH₃ 143 S2-pyrazol-1-yl-benzyl H H H —C(O)NHCH₃ 144 S 2-dimethylaminobenzyl H H H—C(O)NHCH₃ 145 S 2,6-dimethoxybenzyl H H H —C(O)NHCH₃ 146 S2,5-dimethoxybenzyl H H H —C(O)NHCH₃ 147 S 2,3-difluorobenzyl H H H—C(O)NHCH₃ 148 S cycloheptylmethyl H H H —C(O)NHCH₃ 149 S2,6-difluorobenzyl H H H —C(O)NHCH₃ 150 S Pyridin-2-ylmethyl H H H—C(O)NHCH₃ 151 S 3,4-dimethoxybenzyl H H H —C(O)NHCH₃ 152 S2,3-dihydrobenzo- H H H —C(O)NHCH₃ [1,4]dioxin-5-ylmethyl 153 S2-piperidin-1-yl-benzyl H H H —C(O)NHCH₃ 154 S Pyridin-3-ylmethyl H H H—C(O)NHCH₃ 155 S (1R,2R)-2- H H H —C(O)NHCH₃ benzyloxycyclohexyl 156 S(1S,2S)-2- H H H —C(O)NHCH₃ benzyloxycyclohexyl 157 S (1R,2R)-2- H H H—C(O)NHCH₃ hydroxycyclohexyl 158 S 2,6-dichlorobenzyl H H H —C(O)NHCH₃159 S cyclohexylmethyl H H H —C(O)NH(CH₂)₂OCH₃ 160 S cyclohexylmethyl HH H —C(O)NH(CH₂)₂N(CH₃)₂ 161 S 4-sulfonamido-benzyl H H H —C(O)NHCH₃

Representative compounds of Formula (I) include, for example,

-   4-[2-(4-Bromo-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-1-Phenyl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Morpholin-4-yl-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[6-(6,7-dimethoxy-quinolin-4-yloxy)-benzooxazol-2-yl]-amine,-   4-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(1-Thiazol-2-yl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((S)-1-Phenyl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Chloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,4-Dichloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(3-Methyl-cyclohexylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Methoxy-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Ethoxy-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1S,2S,3S,5R)-2,6,6-Trimethyl-bicyclo[3.1.1]hept-3-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   [6-(6,7-Dimethoxy-quinolin-4-yloxy)-benzooxazol-2-yl]-((R)-1-phenyl-ethyl)-amine,-   4-{2-[((1S,2R,4R)-7,7-Dimethyl-bicyclo[2.2.1]hept-2-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Fluoro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Methoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-1-Naphthalen-1-yl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-1-Phenyl-propylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((S)-1-Naphthalen-2-yl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-(2-Cyclobutylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-(2-Cyclopentylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic    acid methylamide,-   4-(2-Cyclohexylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-[2-(2-Morpholin-4-ylmethyl-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-(2-Phenylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-[2-(4-Chloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,4-Dimethoxy-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   N-[4-(2-Cyclohexylamino-benzooxazol-6-yloxy)-pyridin-2-yl]-acetamide,-   4-[2-(Tetrahydro-pyran-4-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(R)-1-(2-Methoxy-phenyl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   N-{4-[2-(2-Chloro-benzylamino)-benzooxazol-6-yloxy]-pyridin-2-yl}-acetamide,-   4-[2-(2,5-Difluoro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   N-{4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridin-2-yl}-acetamide,-   (R)-[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-phenyl-acetic    acid,-   4-{2-[((R)-Methylcarbamoyl-phenyl-methyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-2-Hydroxy-1-phenyl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   (S)-[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-phenyl-acetic    acid,-   4-{2-[((S)-Methylcarbamoyl-phenyl-methyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Pyridin-2-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-(2-Benzylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-[2-(3-Chloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[2-(2-Pyrrolidin-1-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[2-(2-Piperidin-1-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[2-(4-Methyl-imidazol-1-yl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Oxazol-5-yl-phenylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[2-(2-Methyl-imidazol-1-yl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-(2-Amino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-(2-Hydroxy-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-{2-[2-(2-Morpholin-4-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1S,2R)-2-Hydroxy-indan-1-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1R,2S)-2-Hydroxy-indan-1-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-3-Hydroxy-1-phenyl-propylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1S,2S)-2-Hydroxy-cyclohexylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   (R)-[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-phenyl-acetic    acid methyl ester,-   4-[2-((R)-1-Cyclohexyl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   (S)-[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-phenyl-acetic    acid methyl ester,-   4-[2-((S)-2-Hydroxy-1-phenyl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Pyridin-4-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[3-(2-Piperidin-1-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Pyridin-3-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid,-   4-(2-Phenethylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-{2-[((R)-Cyclohexyl-methylcarbamoyl-methyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Pyrrolidin-1-yl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Piperidin-1-yl-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-((S)-1-Cyclohexyl-2-hydroxy-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-1-Cyclohexyl-2-hydroxy-ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   N′-{4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carbonyl}-hydrazine-carboxylic    acid tert-butyl ester,-   4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid amide,-   4-[2-(Cyclohex-3-enylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,4-Difluoro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Bromo-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Fluoro-5-methoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[3-(2-Morpholin-4-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-methyl}-cyclohexane-carboxylic    acid ethyl ester,-   4-[2-(2,6-Dichloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,3-Dichloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Chloro-6-fluoro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,3-Difluoro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   {4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridin-2-yl}-methanol,-   Cyclohexylmethyl-[6-(2-[1,3,4]oxadiazol-2-yl-pyridin-4-yloxy)-benzooxazol-2-yl]-amine,-   4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carbonitrile,-   4-[2-(2,5-Dimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,6-Dimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Dimethylamino-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Amino-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,6-Difluoro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Morpholin-4-yl-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Methyl-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(3,4-Dimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,3-Dimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,4-Dimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-methyl}-cyclohexane-carboxylic    acid,-   4-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(Benzo[1,3]dioxol-5-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Ethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Trifluoromethyl-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-(2-Isopropylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-(2-Isobutylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-(2-tert-Butylamino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-[2-(Cycloheptylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(1-Benzyl-piperidin-4-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(1,2,3,4-Tetrahydro-naphthalen-1-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Pyrazol-1-yl-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(Benzyl-methyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(1-Phenyl-piperidin-4-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   Cyclohexylmethyl-{6-[2-(5-methyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-benzooxazol-2-yl}-amine,-   4-{2-[(2,3-Dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   [6-(2-Aminomethyl-pyridin-4-yloxy)-benzooxazol-2-yl]-cyclohexylmethyl-amine,-   4-{2-[(1-Methylcarbamoyl-cyclohexylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,4,6-Trimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(5-Chloro-2-methoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(5-Fluoro-2-methoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Fluoro-6-methoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Chloro-3,4-dimethoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Piperidin-1-yl-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(4-Benzyl-morpholin-2-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Chloro-6-methoxy-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide, and-   4-{2-[1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide.

Representative compounds of Formula (I) include, for example,

-   4-[2-(4-Chloro-3-trifluoromethyl-phenylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Chloro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(Cyclohexylmethyl-amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(R)-1-(2-Methoxy-phenyl)-ethylamino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,4-Dichloro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-1-Phenyl-ethylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Methoxy-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-(2-Phenethylamino-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid    methylamide,-   4-[2-(2,3-Dichloro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-(2-Cyclohexylamino-benzothiazol-6-yloxy)-pyridine-2-carboxylic    acid methylamide,-   4-[2-(3-Methyl-cyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1S,2S)-2-Hydroxy-cyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((R)-1-Cyclohexyl-ethylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,5-Difluoro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Fluoro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Tetrahydro-pyran-4-ylmethyl)-amino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Morpholin-4-yl-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Pyrazol-1-yl-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Dimethylamino-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,6-Dimethoxy-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,5-Dimethoxy-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,3-Difluoro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(Cycloheptylmethyl-amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,6-Difluoro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Pyridin-2-ylmethyl)-amino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(3,4-Dimethoxy-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-amino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2-Piperidin-1-yl-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-{2-[(Pyridin-3-ylmethyl)-amino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1R,2R)-2-Benzyloxy-cyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1S,2S)-2-Benzyloxy-cyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-((1R,2R)-2-Hydroxy-cyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide,-   4-[2-(2,6-Dichloro-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide, and-   4-[2-(4-Sulfonamido-benzylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic    acid methylamide or a pharmaceutically acceptable salt, tautomer,    solvate, or stereoisomer thereof.

In other embodiments, provided is a compound of Table 2, 3, or 4 or astereoisomer, tautomer, solvate, oxide, ester, prodrug, orpharmaceutically acceptable salt thereof.

It will also be apparent to those skilled in the art that the compoundsof the invention, including the compounds of compounds of Formulas (I),(IIa), (IIb), (IIIa), (IIIb), (IV), or (V) or their stereoisomers, aswell as the pharmaceutically acceptable salts, esters, metabolites andprodrugs of any of them, may be subject to tautomerization and maytherefore exist in various tautomeric forms wherein a proton of one atomof a molecule shifts to another atom and the chemical bonds between theatoms of the molecules are consequently rearranged. See, e.g., March,Advanced Organic Chemistry Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992).

Preferred embodiments, including the compounds of Formulas (I), (IIa),(IIb), (IIIa), (IIIb), (IV), or (V) or their tautomers, as well as thepharmaceutically acceptable salts, esters, metabolites and prodrugs ofany of them, may comprise asymmetrically substituted carbon atoms. Suchasymmetrically substituted carbon atoms can result in the compounds ofpreferred embodiments existing in enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, such as in (R)- or (S)-forms. As a result, all suchpossible isomers, individual stereoisomers in their optically pureforms, mixtures thereof, racemic mixtures (or “racemates”), mixtures ofdiastereomers, as well as single diastereomers of the compounds of thepreferred embodiments are contemplated. The terms “S” and “R”configuration, as used herein, are as defined by the IUPAC 1974RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY , Pure Appl.Chem. 45:13-30 (1976). The terms α and β are employed for ring positionsof cyclic compounds. The α-side of the reference plane is that side onwhich the preferred substituent lies at the lower numbered position.Those substituents lying on the opposite side of the reference plane areassigned β descriptor. It should be noted that this usage differs fromthat for cyclic stereoparents, in which “α” means “below the plane” anddenotes absolute configuration. The terms α and β configuration, as usedherein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE-APPENDIX IV(1987) paragraph 203.

Methods for Treating CSF-1R Mediated Diseases

There are 3 distinct mechanisms by which CSF-1R signaling is likelyinvolved in tumor growth and metastasis. The first is that expression ofCSF-ligand and receptor has been found in tumor cells originating in thefemale reproductive system (breast, ovarian, endometrium, cervical)(Scholl 1994; Kacinski 1997; Nagan 199; Kirma 2007) and the expressionhas been associated with breast cancer xenograft growth as well as poorprognosis in breast cancer patients. Two point mutations were seen inCSF-1R in about 10-20% of acute myelocytic leukemia, chronic myelocyticleukemia and myelodysplasia patients tested in one study, and one ofmutations was found to disrupt receptor turnover (Ridge 1990). Howeverthe incidence of the mutations could not be confirmed in later studies(Abu-Duhier 2003). Mutations were also found in some cases ofhepatocellular cancer (Yang 2004) and idiopathic myelofibrosis(Abu-Duhier 2003).

Pigmented villonodular synovitis (PVNS) and Tenosynovial Giant celltumors (TGCT) can occur as a result of a translocation that fuses theM-CSF gene to a collagen gene COL6A3 and results in overexpression ofM-CSF (West 2006). A landscape effect is proposed to be responsible forthe resulting tumor mass that consists of monocytic cells attracted bycells that express M-CSF. TGCTs are smaller tumors that can berelatively easily removed from fingers where they mostly occur. PVNS ismore aggressive as it can recur in large joints and is not as easilycontrolled surgically.

The second mechanism is based on blocking signaling through M-CSF/CSF-1Rat metastatic sites in bone which induces osteoclastogenesis, boneresorption and osteolytic bone lesions. Breast, kidney, and lung cancersare examples of cancers that have been found to metastasize to the boneand cause osteolytic bone disease resulting in skeletal complications.M-CSF released by tumor cells and stroma induces the differentiation ofhematopoietic myeloid monocyte progenitors to mature osteoclasts incollaboration with the receptor activator of nuclear factor kappa-Bligand—RANKL. During this process, M-CSF acts as a permissive factor bygiving the survival signal to osteoclasts (Tanaka 1993). Inhibition ofCSF-1R kinase activity during osteoclast differentiation and maturationwith a small molecule inhibitor is likely to prevent unbalanced activityof osteoclasts that cause osteolytic disease and the associated skeletalrelated events in metastatic disease. Whereas breast, lung cancer andmultiple myeloma typically result in osteolytic lesions, metastasis tothe bone in prostate cancer initially has an osteoblastic appearance inwhich increased bone forming activity results in ‘woven bone’ which isdifferent from typical lamellar structure of normal bone. During diseaseprogression bone lesions display a significant osteolytic component aswell as high serum levels of bone resorption and suggests thatanti-resorptive therapy may be useful. Bisphosphonates have been shownto inhibit the formation of osteolytic lesions and reduced the number ofskeletal-related events only in men with hormone-refractory metastaticprostate cancer but at this point their effect on osteoblastic lesionsis controversial and bisphosphonates have not been beneficial inpreventing bone metastasis or hormone responsive prostate cancer todate. The effect of anti-resorptive agents in mixedosteolytic/osteoblastic prostate cancer is still being studied in theclinic (Choueiri 2006; Vessella 2006).

The third mechanism is based on the recent observation that tumorassociated macrophages (TAM) found in solid tumors of the breast,prostate, ovarian and cervical cancers correlated with poor prognosis(Bingle 2002; Pollard 2004). Macrophages are recruited to the tumor byM-CSF and other chemokines. The macrophages can then contribute to tumorprogression through the secretion of angiogenic factors, proteases andother growth factors and cytokines and may be blocked by inhibition ofCSF-1R signaling. Recently it was shown by Zins et al (Zins 2007) thatexpression of siRNA of Tumor necrosis factor alpha (TNFα), M-CSF or thecombination of both would reduce tumor growth in a mouse xenograft modelbetween 34% and 50% after intratumoral injection of the respective siRNAinto the xenograft. SiRNA targeting the TNFα secreted by the human SW620cells reduced the mouse M-CSF and led to reduction of macrophages in thetumor. In addition treatment of MCF7 tumor xenografts with an antigenbinding fragment directed against M-CSF antibody did result in 40% tumorgrowth inhibition, reversed the resistance to chemotherapeutics andimproved survival of the mice when given in combination withchemotherapeutics (Paulus 2006).

TAMs are only one example of an emerging link between chronicinflammation and cancer. There is additional evidence for a link betweeninflammation and cancer as many chronic diseases are associated with anincreased risk of cancer; cancers arise at sites of chronicinflammation, chemical mediators of inflammation are found in manycancers; deletion of the cellular or chemical mediators of inflammationinhibits development of experimental cancers and long-term use ofanti-inflammatory agents reduce the risk of some cancers. A link tocancer exists for a number of inflammatory conditions among those H.pylori induced gastritis for gastric cancer, Schistosomiasis for bladdercancer, HHV8 for Kaposi's sarcoma, endometriosis for ovarian cancer andprostatitis for prostate cancer (Balkwill 2005). Macrophages are keycells in chronic inflammation and respond differentially to theirmicroenvironment. There are two types of macrophages that are consideredextremes in a continuum of functional states: M1 macrophages areinvolved in Type 1 reactions. These reactions involve the activation bymicrobial products and consequent killing of pathogenic microorganismsthat result in reactive oxygen intermediates. On the other end of theextreme are M2 macrophages involved in Type 2 reactions that promotecell proliferation, tune inflammation and adaptive immunity and promotetissue remodeling, angiogenesis and repair (Mantovani 2004). Chronicinflammation resulting in established neoplasia is usually associatedwith M2 macrophages. A pivotal cytokine that mediates inflammatoryreactions is TNF-α that true to its name can stimulate anti-tumorimmunity and hemorrhagic necrosis at high doses but has also recentlybeen found to be expressed by tumor cells and acting as a tumor promoter(Zins 2007; Balkwill 2006). The specific role of macrophages withrespect to the tumor still needs to be better understood including thepotential spatial and temporal dependence on their function and therelevance to specific tumor types.

In another embodiment, a method for treating periodontitis,histiocytosis X, osteoporosis, Paget's disease of bone (PDB), bone lossdue to cancer therapy, periprosthetic osteolysis, glucocorticoid-inducedosteoporosis, rheumatoid arthritis, psiratic arthritis, osteoarthritis,inflammatory arthridities, and inflammation is provided.

Rabello 2006 has demonstrated that SNPs in the CSF1 gene exhibited apositive association with aggressive periodontitis: an inflammatorydisease of the periodontal tissues that causes tooth loss due toresorption of the alveolar bone.

Histiocytosis X (also called Langerhans cell histiocytosis, LCH) is aproliferative disease of Langerhans dendritic cells that appear todifferentiate into osteoclasts in bone and extraosseous LCH lesions.Langerhans cells are derived from circulating monocytes (Ginoux 2006).Increased levels of M-CSF that have been measured in sera and lesionswhere found to correlate with disease severity (da Costa 2005). Thedisease occurs primarily in a pediatric patient population and has to betreated with chemotherapy when the disease becomes systemic or isrecurrent.

The pathophysiology of osteoporosis is mediated by loss of bone formingosteoblasts and increased osteoclast dependent bone resorption.Supporting data has been described by Cenci et al showing that ananti-M-CSF antibody injection preserves bone density and inhibits boneresorption in ovarectomized mice (Cenci 2000). Recently a potential linkbetween postmenopausal bone loss due to estrogen deficiency wasidentified and found that the presence of TNFα-producing T-cell affectedbone metabolism (Roggia 2004). A possible mechanism could be theinduction of M-CSF by TNF alpha in vivo. An important role for M-CSF inTNFα-induced osteoclastogenesis was confirmed by the effect of anantibody directed against the M-CSF-inhibitor that blocked theTNFα-induced osteolysis in mice and thereby making inhibitors of CSF-1Rsignaling potential targets for inflammatory arthritis (Kitaura 2005).

Paget's disease of bone (PDB) is the 2^(nd) most common bone metabolismdisorder after osteoporosis in which focal abnormalities of increasedbone turnover lead to complications such as bone pain, deformity,pathological fractures, and deafness. Mutations in four genes have beenidentified that regulate normal osteoclast function and predisposeindividuals to PDB and related disorders: insertion mutations inTNFRSF11A, which encodes receptor activator of nuclear factor (NF)kappaB (RANK)—a critical regulator of osteoclast function, inactivatingmutations of TNFRSF11B which encodes osteoprotegerin (a decoy receptorfor RANK ligand), mutations of the sequestosome 1 gene (SQSTM1), whichencodes an important scaffold protein in the NFkappaB pathway andmutations in the valosin-containing protein (VCP) gene. This geneencodes VCP, which has a role in targeting the inhibitor of NFkappaB fordegradation by the proteasome (Daroszewska, 2006). Targeted CSF-1Rinhibitors provide an opportunity to block the deregulation of the RANKLsignaling indirectly and add an additional treatment option to thecurrently used bisphosphonates.

Cancer therapy induced bone loss especially in breast and prostatecancer patients is an additional indication where a targeted CSF-1Rinhibitor could prevent bone loss (Lester 2006). With the improvedprognosis for early breast cancer the long-term consequences of theadjuvant therapies become more important as some of the therapiesincluding chemotherapy, irradiation, aromatase inhibitors and ovaryablation affect bone metabolism by decreasing the bone mineral density,resulting in increased risk for osteoporosis and associated fractures(Lester 2006). The equivalent to adjuvant aromatase inhibitor therapy inbreast cancer is androgen ablation therapy in prostate cancer whichleads to loss of bone mineral density and significantly increases therisk of osteoporosis-related fractures (Stoch 2001).

Targeted inhibition of CSF-1R signaling is likely to be beneficial inother indications as well when targeted cell types include osteoclastsand macrophages e.g. treatment of specific complications in response tojoint replacement as a consequence of rheumatoid arthritis. Implantfailure due to periprosthetic bone loss and consequent loosing ofprostheses is a major complication of joint replacement and requiresrepeated surgery with high socioeconomic burdens for the individualpatient and the health-care system. To date, there is no approved drugtherapy to prevent or inhibit periprosthetic osteolysis (Drees 2007).

Glucocorticoid-induced osteoporosis (GIOP) is another indication inwhich a CSF-1R inhibitor could prevent bone loss after longtermglucocorticocosteroid use that is given as a result of variousconditions among those chronic obstructive pulmonary disease, asthma andrheumatoid arthritis (Guzman-Clark 2007; Feldstein 2005).

Rheumatoid arthritis, psoriatic arthritis and inflammatory arthriditiesare in themselves potential indications for CSF-1R signaling inhibitorsin that they consist of a macrophage component, and to a varying degree,bone destruction (Ritchlin 2003). Osteoarthritis and rheumatoidarthritis are inflammatory autoimmune diseases caused by theaccumulation of macrophages in the connective tissue and infiltration ofmacrophages into the synovial fluid, which is at least partiallymediated by M-CSF. Campbell et al. (2000) demonstrated that M-CSF isproduced by human-joint tissue cells (chondrocytes, synovialfibroblasts) in vitro and is found in synovial fluid of patients withrheumatoid arthritis, suggesting that it contributes to the synovialtissue proliferation and macrophage infiltration which is associatedwith the pathogenesis of the disease. Inhibition of CSF-1R signaling islikely to control the number of macrophages in the joint and alleviatepain from the associated bone destruction. In order to minimize adverseaffects and to further understand the impact of the CSF-1R signaling inthese indications, one method is to specifically inhibit CSF-1R withouttargeting a myriad other kinases, such as Raf kinase.

Recent literature reports correlate increased circulating M-CSF withpoor prognosis and atherosclerotic progression in chronic coronaryartery disease (Saitoh 2000; Ikonomidis 2005); M-CSF influences theatherosclerotic process by aiding the formation of foam cells(macrophages with ingested oxidized LDL) that express CSF-1R andrepresent the initial plaque (Murayama 1999).

Expression and signaling of M-CSF and CSF-1R is found in activatedmicroglia. Microglia, which are resident macrophages of the centralnervous system, can be activated by various insults, including infectionand traumatic injury. M-CSF is considered a key regulator ofinflammatory responses in the brain and M-CSF levels increase in HIV-1encephalitis, Alzheimer's disease (AD) and brain tumors. Microgliosis asa consequence of autocrine signaling by M-CSF/CSF-1R results ininduction of inflammatory cytokines and nitric oxides being released asdemonstrated by e.g. using an experimental neuronal damage model (Hao2002; Murphy 1998). Microglia that have increased expression of CSF-1Rare found to surround plaques in AD and in the amyloid precursor proteinV717F transgenic mouse model of AD (Murphy 2000). On the other handop/op mice with fewer microglia in the brain resulted in fibrilardeposition of Aβ and neuronal loss compared to normal control suggestingthat microglia do have a neuroprotective function in the development ofAD lacking in the op/op mice (Kaku 2003).

In one aspect, the preferred embodiments provide methods for treatingCSF-1R related disorders in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V)effective to reduce or prevent the disorder. In a preferred embodiment,the disorder is tumor growth and/or metathesis in the subject.

In other aspects, the preferred embodiments provide methods for treatingCSF-1R related disorders in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V)effective to reduce or prevent osteoclastogenesis, bone resorptionand/or bone lesions in the subject.

In yet other aspects, the preferred embodiments provide methods fortreating CSF-1R related disorders in a human or animal subject in needof such treatment comprising administering to said subject an amount ofa compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V)effective to treat the disorder in the subject in combination with atleast one additional agent. In a more particular embodiment theadditional agent is a bisphosphonate. In one embodiment the disorder istumor growth and/or metastasis, osteoclastogenesis, bone resorptionand/or bone lesions

In yet other aspects, the preferred embodiments provide compounds ofFormula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V) that are capableof selectively or preferentially inhibiting CSF-1R. In preferredembodiments the selective inhibitors of CSF-1R are capable of inhibitingCSF-1R at greater than about 5-fold, or about 10 fold, or about 20 fold,or about 30 fold, or about 50 fold, or about 100 fold, or about 250fold, or about 500 fold, or about 750 fold, or about 1,000 fold, orabout 2,000 the inhibitory activity (with respect to IC₅₀ values, forexample) in Raf kinase.

In other aspects provided is a method of inhibiting CSF-1R comprisingcontacting a cell with a compound of Formula (I), (IIa), (IIb), (IIIa),(IIIb), (IV), or (V). In some aspects said compound is4-{2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide or4-[2-((1R,2R)-2-Benzyloxy-cyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylicacid methylamide.

In one aspect, the inhibitory effect of compounds on Raf is determinedusing the following biotinylated assay. The Raf kinase activity ismeasured by providing ATP, a recombinant kinase inactive MEK substrateand assaying the transfer of phosphate moiety to the MEK residue.Recombinant full length MEK with an inactivating K97R ATP binding sitemutation (rendering kinase inactive) is expressed in E. coli andlabelled with biotin post purification. The MEK cDNA is subcloned withan N-terminal (His)₆ tag and expressed in E. coli and the recombinantMEK substrate is purified from E. coli lysate by nickel affinitychromatography followed by anion exchange. The final MEK substratepreparation is biotinylated (Pierce EZ-Link Sulfo-NHS-LC-Biotin) andconcentrated to about 11.25 μM. Recombinant Raf (including c-Raf andmutant B-Raf isoforms) is obtained by purification from sf9 insect cellsinfected with the corresponding human Raf recombinant expressionvectors. The recombinant Raf isoforms are purified via a Glu antibodyinteraction or by Metal Ion Chromatography.

For each assay, the compound is serially diluted, for instance, startingat 25 μM with 3-fold dilutions, in DMSO and then mixed with various Rafisoforms (about 0.50 nM each). The kinase inactive biotin-MEK substrate(50 nM) is added in reaction buffer plus ATP (1 μM). The reaction buffercontains 30 mM Tris-HCl₂ pH 7.5, 10 mM MgCl₂, 2 mM DTT, 4 mM EDTA, 25 mMbeta-glycerophosphate, 5 mM MnCl₂, and 0.01% BSA/PBS. Reactions aresubsequently incubated for about 2 hours at room temperature and stoppedby the addition of 0.5 M EDTA. Stopped reaction mixture is transferredto a neutradavin-coated plate and incubated for about 1 hour.Phosphorylated product is measured with the DELFIA time-resolvedfluorescence system, using a rabbit anti-p-MEK (Cell Signaling) as theprimary antibody and europium labeled anti-rabbit as the secondaryantibody. Time resolved fluorescence can be read on a Wallac 1232 DELFIAfluorometer. The concentration of the compound for 50% inhibition (IC₅₀)is calculated by non-linear regression using XL Fit data analysissoftware.

In yet other aspects, the preferred embodiments provide methods fortreating CSF-1R related disorders in a human or animal subject in needof such treatment comprising administering to said subject an amount ofa compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V)effective to reduce or prevent tumor growth in the subject incombination with at least one additional agent for the treatment ofcancer. In a more particular embodiment the additional agent is abisphosphonate.

A number of suitable anticancer agents to be used as combinationtherapeutics are contemplated for use in the methods of the preferredembodiments. Indeed, the preferred embodiments include administration ofnumerous additional anticancer agents such as, but not limited to,agents that induce apoptosis; polynucleotides (e.g., ribozymes);polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids;alkylating agents; antitumor antibiotics; antimetabolites; hormones;platinum compounds; monoclonal antibodies conjugated with anticancerdrugs, toxins, and/or radionuclides; biological response modifiers (e.g.interferons [e.g. IFN-α, etc.] and interleukins [e.g. IL-2, etc.],etc.); adoptive immunotherapy agents; hematopoietic growth factors;agents that induce tumor cell differentiation (e.g. all-trans-retinoicacid, etc.); gene therapy reagents; antisense therapy reagents andnucleotides; tumor vaccines; inhibitors of angiogenesis, and the like.Numerous other examples of chemotherapeutic compounds and anticancertherapies suitable for coadministration with the disclosed compounds ofFormula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V) are known tothose skilled in the art.

In preferred embodiments, additional anticancer agents to be used incombination with compounds of the preferred embodiments comprise agentsthat induce or stimulate apoptosis. Agents that induce apoptosisinclude, but are not limited to, radiation (e.g., ω); kinase inhibitors(e.g., Epidermal Growth Factor Receptor [EGFR] kinase inhibitor,Vascular Endothelial Growth Factor Receptor [VEGFR] kinase inhibitor,Fibroblast Growth Factor Receptor [FGFR] kinase inhibitor,Platelet-derived Growth Factor Receptor [PDGFR] I kinase inhibitor, andBcr-Abl kinase inhibitors such as STI-571, Gleevec, and Glivec]);antisense molecules; antibodies [e.g., Herceptin and Rituxan];anti-estrogens [e.g., raloxifene and tamoxifen]; anti-androgens [e.g.,flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole,and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [e.g.,Celecoxib, meloxicam, NS-398, and non-steroidal antiinflammatory drugs(NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan(Camptosar), CPT-11, fludarabine (Fludara), dacarbazine (DTIC),dexamethasone, mitoxantrone, Mylotarg, VP-16, cisplatinum, 5-FU,Doxrubicin, Taxotere or taxol; cellular signaling molecules; ceramidesand cytokines; and staurosprine, and the like.

The compounds of the preferred embodiments are useful in vitro or invivo in inhibiting the growth of cancer cells. The compounds may be usedalone or in compositions together with a pharmaceutically acceptablecarrier or excipient.

In other aspects, the preferred embodiments provide pharmaceuticalcompositions comprising at least one compound of Formula (I), (IIa),(IIb), (IIIa), (IIIb), (IV), or (V) together with a pharmaceuticallyacceptable carrier suitable for administration to a human or animalsubject, either alone or together with other anticancer agents.

In other aspects, the preferred embodiments provide methods ofmanufacture of compounds of Formula (I), (IIa), (IIb), (IIIa), (IIIb),(IV), or (V) as described herein.

In other aspects provided is a pharmaceutical composition comprising aneffective amount of a compound, stereoisomer, tautomer, solvate, oxide,ester, or prodrug of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or(V) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. In some aspects the compound preferentially inhibitsCSF-1R over Raf kinase. More particularly said compound inhibits Rafkinase at greater than about 1 μM.

Other aspects further comprise an additional agent. More particularly,said additional agent is a bisphosphonate.

Other aspects provide compounds of Formula (I), (IIa), (IIb), (IIIa),(IIIb), (IV), or (V) effective to inhibit CSF-1R activity in a human oranimal subject when administered thereto. More particularly, saidcompound exhibits an IC₅₀ value with respect to CSF-1R inhibition ofless than about 1 μM. More particularly, said compound exhibits an IC₅₀value with respect to Raf inhibition of greater than about 1 μM.

Another embodiment provides a method of inhibiting CSF-1R, wherein saidcompound selectively inhibits CSF-1R.

The compounds of the embodiments are useful in vitro or in vivo ininhibiting the growth of cancer cells. The compounds may be used aloneor in compositions together with a pharmaceutically acceptable carrieror excipient. Suitable pharmaceutically acceptable carriers orexcipients include, for example, processing agents and drug deliverymodifiers and enhancers, such as, for example, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, lowmelting waxes, ion exchange resins, and the like, as well ascombinations of any two or more thereof. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey (1991), incorporated herein byreference.

Administration and Pharmaceutical Composition

In general, the compounds of preferred embodiments will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of preferred embodiments, i.e., the activeingredient, will depend upon numerous factors such as the severity ofthe disease to be treated, the age and relative health of the subject,the potency of the compound used, the route and form of administration,and other factors. The drug can be administered more than once a day,preferably once or twice a day. All of these factors are within theskill of the attending clinician.

Effective amounts of the compounds of the preferred embodimentsgenerally include any amount sufficient to detectably inhibit CSF-1Ractivity by any of the assays described herein, by other CSF-1R kinaseactivity assays known to those having ordinary skill in the art or bydetecting an inhibition or alleviation of symptoms of cancer.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The therapeutically effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

For purposes of the preferred embodiments, a therapeutically effectivedose generally can be a total daily dose administered to a host insingle or divided doses may be in amounts, for example, of from about0.001 to about 1000 mg/kg body weight daily and more preferred fromabout 1.0 to about 30 mg/kg body weight daily. Dosage unit compositionsmay contain such amounts of submultiples thereof to make up the dailydose.

The choice of formulation depends on various factors such as the mode ofdrug administration and bioavailability of the drug substance. Ingeneral, compounds of preferred embodiments can be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen that can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions. Another preferred manner for administering compounds ofpreferred embodiments is inhalation. This is an effective method fordelivering a therapeutic agent directly to the respiratory tract (seeU.S. Pat. No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include, forexample, processing agents and drug delivery modifiers and enhancers,such as, for example, calcium phosphate, magnesium stearate, talc,monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose,hydroxypropyl-β-cyclodextrin, polyvinyl-pyrrolidinone, low meltingwaxes, ion exchange resins, and the like, as well as combinations of anytwo or more thereof. Liquid and semisolid excipients can be selectedfrom glycerol, propylene glycol, water, ethanol and various oils,including those of petroleum, animal, vegetable or synthetic origin,e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferredliquid carriers, particularly for injectable solutions, include water,saline, aqueous dextrose, and glycols. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey (1991), incorporated herein byreference.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds ofFormulas (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or (V). These saltscan be prepared in situ during the final isolation and purification ofthe compounds of Formulas (I), (IIa), (IIb), (IIIa), (IIIb), (IV), or(V), or by separately reacting the base or acid functions with asuitable organic or inorganic acid or base, respectively. Representativesalts include, but are not limited to, the following: acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemi-sulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate,sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.Also, the basic nitrogen-containing groups can be quaternized withagents such as alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of Formulas (I),(IIa), (IIb), (IIa), (IIIb), (IV), or (V), or separately by reactingcarboxylic acid moieties with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia, or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium, aluminum salts and the like, aswell as nontoxic ammonium, quaternary ammonium, and amine cations,including, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. Other representative organicamines useful for the formation of base addition salts includediethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazineand the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters, which hydrolyze in vivo and include those that break downreadily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the preferred embodiments which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theembodiments. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

It will be apparent to those skilled in the art that the compounds ofthe preferred embodiments, including the compounds of Formulas (I),(IIa), (IIb), (IIIa), (IIIb), (IV), or (V) or their tautomers, prodrugs,and stereoisomers, as well as the pharmaceutically acceptable salts,esters and prodrugs of any of them, may be processed in vivo throughmetabolism in a human or animal body or cell to produce metabolites. Theterm “metabolite” as used herein refers to the formula of any derivativeproduced in a subject after administration of a parent compound. Thederivatives may be produced from the parent compound by variousbiochemical transformations in the subject such as, for example,oxidation, reduction, hydrolysis, or conjugation and include, forexample, oxides and demethylated derivatives. The metabolites of acompound of the embodiments may be identified using routine techniquesknown in the art. See, e.g., Bertolini, G. et al., J. Med. Chem.40:2011-2016 (1997); Shan, D. et al., J. Pharm. Sci. 86(7):765-767;Bagshawe K., Drug Dev. Res. 34:220-230 (1995); Bodor, N., Advances inDrug Res. 13:224-331 (1984); Bundgaard, H., Design of Prodrugs (ElsevierPress 1985); and Larsen, I. K., Design and Application of Prodrugs, DrugDesign and Development (Krogsgaard-Larsen et al., eds., Harwood AcademicPublishers, 1991). It should be understood that individual chemicalcompounds that are metabolites of the compounds of Formulas (I), (IIa),(IIb), or (III) or their tautomers, prodrugs, and stereoisomers, as wellas the pharmaceutically acceptable salts, esters and prodrugs of any ofthem, are included within the preferred embodiments.

The compounds of the preferred embodiments may be administered orally,parenterally, sublingually, by aerosolization or inhalation spray,rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intrathecal, intramuscular,intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols, which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the preferred embodiments can also be administered inthe form of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the preferred embodiments, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., p.33 et seq. (1976).

Compressed gases may be used to disperse a compound of preferredembodiments in aerosol form. Inert gases suitable for this purpose arenitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipientsand their formulations are described in Remington's PharmaceuticalSciences, edited by E. W. Martin (Mack Publishing Company, 18th ed.,1990).

For delivery via inhalation the compound can be formulated as liquidsolution, suspensions, aerosol propellants or dry powder and loaded intoa suitable dispenser for administration. There are several types ofpharmaceutical inhalation devices-nebulizer inhalers, metered doseinhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices producea stream of high velocity air that causes the therapeutic agents (whichare formulated in a liquid form) to spray as a mist that is carried intothe patient's respiratory tract. MDI's typically are formulationpackaged with a compressed gas. Upon actuation, the device discharges ameasured amount of therapeutic agent by compressed gas, thus affording areliable method of administering a set amount of agent. DPI dispensestherapeutic agents in the form of a free flowing powder that can bedispersed in the patient's inspiratory air-stream during breathing bythe device. In order to achieve a free flowing powder, the therapeuticagent is formulated with an excipient such as lactose. A measured amountof the therapeutic agent is stored in a capsule form and is dispensedwith each actuation.

Recently, pharmaceutical formulations have been developed especially fordrugs that show poor bioavailability based upon the principle thatbioavailability can be increased by increasing the surface area i.e.,decreasing particle size. For example, U.S. Pat. No. 4,107,288 describesa pharmaceutical formulation having particles in the size range fromabout 10 to about 1,000 nm in which the active material is supported ona crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size ofabout 400 nm) in the presence of a surface modifier and then dispersedin a liquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

Combination Therapies

While the compounds of the preferred embodiments can be administered asthe sole active pharmaceutical agent, they can also be used incombination with one or more other agents used in the treatment ofcancer. The compounds of the preferred embodiments are also useful incombination with known therapeutic agents and anti-cancer agents, andcombinations of the presently disclosed compounds with other anti-canceror chemotherapeutic agents are within the scope of the preferredembodiments. Examples of such agents can be found in Cancer Principlesand Practice of Oncology, V. T. Devita and S. Hellman (editors), 6^(th)edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. Aperson of ordinary skill in the art would be able to discern whichcombinations of agents would be useful based on the particularcharacteristics of the drugs and the cancer involved. Such anti-canceragents include, but are not limited to, the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic/cytostatic agents, antiproliferative agents, prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors and otherangiogenesis inhibitors, inhibitors of cell proliferation and survivalsignaling, apoptosis inducing agents and agents that interfere with cellcycle checkpoints. The compounds of the preferred embodiments are alsouseful when co-administered with radiation therapy.

Therefore, in one embodiment, the compounds are also used in combinationwith known anticancer agents including, for example, estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic agents, antiproliferative agents, prenyl-protein transferaseinhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, and other angiogenesis inhibitors.

Estrogen receptor modulators are compounds that can interfere with orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

Androgen receptor modulators are compounds which can interfere with orinhibit the binding of androgens to an androgen receptor. Representativeexamples of androgen receptor modulators include finasteride and other5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole,and abiraterone acetate. Retinoid receptor modulators are compoundswhich interfere or inhibit the binding of retinoids to a retinoidreceptor. Examples of retinoid receptor modulators include bexarotene,tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, LX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N4-carboxyphenyl retinamide.

Cytotoxic and/or cytostatic agents are compounds which can cause celldeath or inhibit cell proliferation primarily by interfering directlywith the cell's functioning or inhibit or interfere with cell mytosis,including alkylating agents, tumor necrosis factors, intercalators,hypoxia activatable compounds, microtubuleinhibitors/microtubule-stabilizing agents, inhibitors of mitotickinesins, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors and ubiquitin ligase inhibitors. Examples of cytotoxic agentsinclude, but are not limited to, sertenef, cachectin, ifosfamide,tasonermin, lonidamine, carboplatin, altretamine, prednimustine,dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin,temozolomide, heptaplatin, estramustine, improsulfan tosilate,trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin,satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride,diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032). A representative example of a hypoxia activatable compoundis tirapazamine. Proteasome inhibitors include, but are not limited to,lactacystin and bortezomib. Examples of microtubuleinhibitors/microtubule-stabilizing agents include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butyl-amide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797. Representative examples of topoisomeraseinhibitors include topotecan, hycaptamine, irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroOxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexa-hydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1′-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna. Examples of inhibitors of mitotic kinesins, such as thehuman mitotic kinesin KSP, are described in PCT Publications WO 01/30768and WO 01/98278, WO 03/050,064 (Jun. 19, 2003), WO 03/050,122 (Jun. 19,2003), WO 03/049,527 (Jun. 19, 2003), WO 03/049,679 (Jun. 19, 2003), WO03/049,678 (Jun. 19, 2003) and WO 03/39460 (May 15, 2003) and pendingPCT Appl. Nos. US03/06403 (filed Mar. 4, 2003), US03/15861 (filed May19, 2003), US03/15810 (filed May 19, 2003), US03/18482 (filed Jun. 12,2003) and US03/18694 (filed Jun. 12, 2003). In an embodiment inhibitorsof mitotic kinesins include, but are not limited to inhibitors of KSP,inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK,inhibitors of Kif14, inhibitors of Mphosph1 and inhibitors of Rab6-KIFL.

Inhibitors of kinases involved in mitotic progression include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (e.g., inhibitors of PLK-1), inhibitors of bub-1 andinhibitors of bub-1R. Antiproliferative agents include antisense RNA andDNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, andINX3001, and antimetabolites such as enocitabine, carmofur, tegafur,pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine,galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate,raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed,pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. Examples ofmonoclonal antibody targeted therapeutic agents include thosetherapeutic agents which have cytotoxic agents or radioisotopes attachedto a cancer cell specific or target cell specific monoclonal antibody.Examples include, for example, Bexxar. HMG-CoA reductase inhibitors areinhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Compounds whichhave inhibitory activity for HMG-CoA reductase can be readily identifiedby using assays well-known in the art such as those described or citedin U.S. Pat. No. 4,231,938 and WO 84/02131. Examples of HMG-CoAreductase inhibitors that may be used include, but are not limited to,lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structuralformulas of these and additional HMG-CoA reductase inhibitors that maybe used in the instant methods are described at page 87 of M. Yalpani,“Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb.1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. In an embodiment, theHMG-CoA reductase inhibitor is selected from lovastatin or simvastatin.

Prenyl-protein transferase inhibitors are compounds which inhibit anyone or any combination of the prenyl-protein transferase enzymes,including farnesyl-protein transferase (FPTase), geranylgeranyl-proteintransferase type I (GGPTase-I), and geranylgeranyl-protein transferasetype-II (GGPTase-II, also called Rab GGPTase). Examples ofprenyl-protein transferase inhibiting compounds include(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)quinolinone,(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl-2-piperazinone,(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl)-2-piperazinone,5(S)-n-butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone,1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,4-{-[4-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{-5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol4-ylmethyl}benzonitrile,4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile,18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile,(±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile,19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile,and(.+−.)-19,20-dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.Other examples of prenyl-protein transferase inhibitors can be found inthe following publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer 35(9):1394-1401 (1999).

Angiogenesis inhibitors refers to compounds that can inhibit theformation of new blood vessels, regardless of mechanism. Examples ofangiogenesis inhibitors include, but are not limited to, tyrosine kinaseinhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1(VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived,fibroblast-derived, or platelet derived growth factors, MMP (matrixmetalloprotease) inhibitors, integrin blockers, interferon-.alpha.,interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors,including nonsteroidal anti-inflammatories (NSAIDs) like aspirin andibuprofen as well as selective cyclooxy-genase-2 inhibitors likecelecoxib and rofecoxib (PNAS 89:7384 (1992); JNCI 69:475 (1982); Arch.Opthalmol. 108:573 (1990); Anat. Rec., (238):68 (1994); FEBS Letters372:83 (1995); Clin, Orthop. 313:76 (1995); J. Mol. Endocrinol. 16:107(1996); Jpn. J. Pharmacol. 75:105 (1997); Cancer Res. 57:1625 (1997);Cell 93:705 (1998); Intl. J. Mol. Med. 2:715 (1998); J. Biol. Chem.274:9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, 17:963-968 (October 1999); Kim etal., Nature, 362:841-844 (1993); WO 00/44777; and WO 00/61186). Othertherapeutic agents that modulate or inhibit angiogenesis and may also beused in combination with the compounds of the preferred embodimentsinclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in PCT Publication WO03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002). Thepreferred embodiments also encompass combinations of the compounds ofthe preferred embodiments with NSAIDs which are selective COX-2inhibitors (generally defined as those which possess a specificity forinhibiting COX-2 over COX-1 of at least about 100 fold as measured bythe ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1 evaluated by cell ormicrosomal assays). Such compounds include, but are not limited to thosedisclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat.No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issuedDec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat.No. 5,409,944, issued Apr. 25, 1995, U.S. Pat. No. 5,436,265, issuedJul. 25, 1995, U.S. Pat. No. 5,536,752, issued Jul. 16, 1996, U.S. Pat.No. 5,550,142, issued Aug. 27, 1996, U.S. Pat. No. 5,604,260, issuedFeb. 18, 1997, U.S. Pat. No. 5,698,584, issued Dec. 16, 1997, U.S. Pat.No. 5,710,140, issued Jan. 20, 1998, WO 94/15932, published Jul. 21,1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994, U.S. Pat. No.5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738, issued Jan.10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S. Pat. No.5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272, issued May 27,1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999, all of which arehereby incorporated by reference. Representative inhibitors of COX-2that are useful in the methods of the preferred embodiments include3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine.Compounds which are described as specific inhibitors of COX-2 and aretherefore useful in the preferred embodiments, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, U.S. Pat. No. 5,932,598, issued Aug. 3, 1999, U.S.Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419,issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999,U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944,issued Apr. 25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995,U.S. Pat. No. 5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142,issued Aug. 27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997,U.S. Pat. No. 5,698,584, issued Dec. 16, 1997, and U.S. Pat. No.5,710,140, issued Jan. 20, 1998. Other examples of angiogenesisinhibitors include, but are not limited to, endostatin, ukrain,ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

Agents that interfere with cell cycle checkpoints are compounds that caninhibit protein kinases that transduce cell cycle checkpoint signals,thereby sensitizing the cancer cell to DNA damaging agents. Such agentsinclude inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk andcdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

Inhibitors of cell proliferation and survival signaling pathway can bepharmaceutical agents that can inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors ofPI3K (for example LY294002), serine/threonine kinases (including but notlimited to inhibitors of Akt such as described in WO 02/083064, WO02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (forexample BAY-43-9006), inhibitors of MEK (for example CI-1040 andPD-098059) and inhibitors of mTOR (for example Wyeth CCI-779). Suchagents include small molecule inhibitor compounds and antibodyantagonists.

Apoptosis inducing agents include activators of TNF receptor familymembers (including the TRAIL receptors).

In certain presently preferred embodiments, representative agents usefulin combination with the compounds of the preferred embodiments for thetreatment of cancer include, for example, irinotecan, topotecan,gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec),anthracyclines, rituximab, trastuzumab, as well as other cancerchemotherapeutic agents.

The above compounds to be employed in combination with the compounds ofthe preferred embodiments can be used in therapeutic amounts asindicated in the Physicians' Desk Reference (PDR) 47th Edition (1993),which is incorporated herein by reference, or such therapeuticallyuseful amounts as would be known to one of ordinary skill in the art.

The compounds of the preferred embodiments and the other anticanceragents can be administered at the recommended maximum clinical dosage orat lower doses. Dosage levels of the active compounds in thecompositions of the preferred embodiments may be varied so as to obtaina desired therapeutic response depending on the route of administration,severity of the disease and the response of the patient. The combinationcan be administered as separate compositions or as a single dosage formcontaining both agents. When administered as a combination, thetherapeutic agents can be formulated as separate compositions, which aregiven at the same time or different times, or the therapeutic agents,can be given as a single composition.

General Synthetic Methods

The compounds of preferred embodiments can be prepared from readilyavailable starting materials using the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999, and references citedtherein.

Furthermore, the compounds of preferred embodiments contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers, or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthe embodiments, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures, orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989),Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley and Sons, 4^(th) Edition), andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The various starting materials, intermediates, and compounds of thepreferred embodiments may be isolated and purified where appropriateusing conventional techniques such as precipitation, filtration,crystallization, evaporation, distillation, and chromatography.Characterization of these compounds may be performed using conventionalmethods such as by melting point, mass spectrum, nuclear magneticresonance, and various other spectroscopic analyses.

Compounds of the embodiments may generally be prepared using a number ofmethods familiar to one of skill in the art, such as, for example, themethods disclosed in U.S. patent application Publication Nos.US20040087626 A1 and US20040122237 A1, the disclosures of which areincorporated herein in their entirety, in connection with the followingdescription and examples. The compounds of the embodiments may begenerally made in accordance with the following reaction Schemes 1-8,which are described in detail in the Examples, below.

Schemes 1-8 illustrate general methods for the preparation ofintermediates and compounds of the embodiments. These compounds areprepared from starting materials either known in the art or arecommercially available. The specific compounds are for illustrativepurposes only.

In Scheme 1, 2-hydroxyaniline or a derivative thereof reacts withethylxanthic acid to give a thiol-benzoxazole. The thiol-benzoxazole isconverted to a chloro-benzoxazole with reaction with thionyl chloride.Alternatively, the thiol benzoxazole can be converted to halogenatedbenzoxazole with a array of halogenating agents, such as, but notlimited to phosphorus trichloride, phosphorus tribromide, phosgene, oroxalyl chloride. The chloro-benzoxazole is then reacted with abenzylamine such as 2-chlorobenzylamine to give abenzylamino-benzoxazole. The benzylamino-benzoxazole is coupled withchloro-pyridine in the presence of a base such as, cesium carbonate togive a compound of the invention. Alternatively, a halogenated pyridinecan be used for the coupling.

In Scheme 2, a thiol-benzoxazole or derivative thereof is alkylated atthe thiol moiety. The alkylated thiol-benzoxazole is coupled with thecorresponding halo pyridine such as chloro-pyridine in the presence of abase such as cesium carbonate to give a compound of the invention. Theresulting benzoxazolyloxy-pyridine is oxidized, for instance, withmCPBA. Other oxidizing agents can be used to oxidize the thiol to asulfoxide. Other oxidizing agents include, but are not limited to,hydrogen peroxide, sodium periodate, pyridinium chlorochromate orchromium trioxide. The sulfoxide of the benzoxazolyloxy-pyridine issubjected to nucleophilic attack with an amine to give a compound of theinvention.

In Scheme 3, cyanoacetate and 1,5-dibromopentane are coupled to form1-cyano-cyclohexanecarboxylic acid ethyl ester after cyclization. Thisproduct is reduced with hydrogen and Raney nickel. Other reducing agentscan be used to reduce the nitrile group to an amine. Other reducingagents include, but are not limited to, catalytic hydrogenation usingplatinum oxide or Raney nickel or lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, or lithium triethylborohydride.The reduced product is coupled with sulfoxo-benzoxazolyloxy-pyridine.The resulting product from the coupling reaction can be furtherfunctionalized or derivatized. For example, in Scheme 3, an ester groupcan be converted to a carboxylic acid group from hydrolysis and thenconverted to an amide from reaction with an amine. These reactions arewell-known conversions to one skilled in the art.

In Scheme 4, 3-(2-piperidin-1-yl-ethyl)-phenylamine is an example of anamine that can be used to form a compound of the embodiments.3-(2-Piperidin-1-yl-ethyl)-phenylamine is formed from sulfonation of2-(3-nitrophenyl)-ethanol, then aminating the resulting methanesulfonicacid 2-(3-nitrophenyl)-ethyl ester, and subsequently reducing theresulting 1-[2-(3-nitrophenyl)-ethyl]-piperidine.

In Scheme 5,4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamideis aminated with cyclohexylmethanamine. The resulting4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamideis then hydrolyzed to form4-[2-(cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylicacid.4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylicacid then reacts withbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate,tert-butyl carbazate, and triethyl amine to form4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide.4-(2-(Cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazidethen reacts with trimethyl orthoformate to form a compound of theembodiments.

In Scheme 6, a compound of the embodiment can be further functionalized.For instance,4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carboxylicacid is reduced to{4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-yl}-methanolwith borane. Other suitable reducing agents include, but are not limitedto, lithium aluminum hydride, aluminum hydride, diisobultyl aluminumhydride, sodium borohydride, or lithium triethylborohydride.{4-(2-(Cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-yl}-methanolis then oxidized to4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbaldehydewith Dess-Martin reagent. Other suitable oxidizing agents include, butare not limited to, pyridinium chlorochromate, SO₃ pyridine in DMSO, orconditions commonly referred to as a Swern or Moffet oxidation.4-(2-(Cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbaldehydeis then converted tocyclohexylmethyl-{6-[2-(5-methyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-benzooxazol-2-yl}-amineby reaction with pyruvic aldehyde.

In Scheme 7, a compound of the embodiments is synthesized from reactionof 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide (from Example 2) with1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine. In one instance,1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine is synthesized via aresin.

An amine linked to a resin is reacted with2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde, thus givingC-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine.C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine is derivatized withalkylation at the imino site, such as with methyl magnesium bromide.Other alkylating agents can be used according to the desired molecule.The resulting 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine iscleaved from the resin. An example of a resin-cleaving agent istrifluoroacetic acid (TFA). The resulting1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine can be used forsynthesis of a compound of the embodiments. For instance,1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine can be used to reactwith 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylicacid methylamide to form4-{2-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide.

In Scheme 8, 2-mercapto-benzothiazol-6-ol was prepared as per U.S. Pat.No. 4,873,346. 2-Mercapto-benzothiazol-6-ol is then converted to2-methylsulfanyl-benzothiazol-6-ol via conventional procedures to removean ethereal protecting group. Reaction of2-methylsulfanyl-benzothiazol-6-ol with methyl iodide providesalkylation at the thiol position. Reaction of2-methylsulfanyl-benzothiazol-6-ol with 4-chloro-pyridine-2-carboxylicacid methylamide gives4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide. Subsequent oxidation of4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide gives4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide.4-(2-Methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide can be a substrate for reaction with various amines. Forinstance,4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide can react with cyclohexylmethylamine to give4-[2-(cyclohexylmethyl-amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylicacid methylamide.

In Scheme 9 benzoxazoles or benzothiazoles of formula 9.1 can be reactedwith a substituted amine to provide intermediates of the formula 9.2.Treatment of intermediates of formula 9.2 with a reagent such as, forexample, BBr₃ provides phenols of the formula 9.3. Subsequent treatmentof intermediates of formula 9.3 with 4-halo pyridines of formula 9.4 attemperatures generally ranging from, but not limited to, roomtemperature to 130° C. provides in the presence of a base such as, forexample, potassium or cesium carbonate provides compounds for formula9.5. Further treatment with boronic acids or stannanes under conditionsknown to those practiced in the art as Suzuki or Stille reactionsprovides compounds of formula 9.6. In addition, treatment of a compoundof formula 9.5 with a substituted amine under conditions known to thosepracticed in the art for a Buchwald reaction or SnAr reaction providescompounds of formula 9.7.

In Scheme 10 benzoxazoles or benzothiazoles of formula 10.5 and 10.6 canbe prepared starting with a 4-halopyridine for formula 10.1 which can be(1) treated with boronic acids or stannanes under conditions known tothose practiced in the art as Suzuki or Stille reactions providesintermediates of formula 10.2 or (2) reacted with a substituted amineunder conditions known to those practiced in the art for a Buchwaldreaction or SnAr reaction to provide intermediates of formula 10.3.Subsequent reaction of intermediates of formula 10.2 or 10.3 with aphenolic intermediate of formula 10.4 in the presence of a base such as,for example, potassium or cesium carbonate in a solvent such as, forexample, dimethyl formamide, acetonitrile or dioxane provides compoundsof formula 10.5 and 10.6.

EXAMPLES

Referring to the examples that follow, compounds of the preferredembodiments were synthesized using the methods described herein, orother methods, which are known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Milleniumchromatography system with a 2695 Separation Module (Milford, Mass.).The analytical columns were reversed phase Phenomenex Luna C18-5μ,4.6×50 mm, from Alltech (Deerfield, Ill.). A gradient elution was used(flow 2.5 mL/min), typically starting with 5% acetonitrile/95% water andprogressing to 100% acetonitrile over a period of 10 minutes. Allsolvents contained 0.1% trifluoroacetic acid (TFA). Compounds weredetected by ultraviolet light (UV) absorption at either 220 or 254 nm.HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or FisherScientific (Pittsburgh, Pa.).

In some instances, purity was assessed by thin layer chromatography(TLC) using glass or plastic backed silica gel plates, such as, forexample, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results werereadily detected visually under ultraviolet light, or by employing wellknown iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two LCMSinstruments: a Waters System (Alliance HT HPLC and a Micromass ZQ massspectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; gradient: 5-95% (or35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA over a4 min period; flow rate 0.8 mL/min; molecular weight range 200-1500;cone Voltage 20 V; column temperature 40° C.) or a Hewlett PackardSystem (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; gradient:5-95% acetonitrile in water with 0.05% TFA over a 4 min period; flowrate 0.8 mL/min; molecular weight range 150-850; cone Voltage 50 V;column temperature 30° C.). All masses were reported as those of theprotonated parent ions.

GCMS analysis is performed on a Hewlett Packard instrument (HP6890Series gas chromatograph with a Mass Selective Detector 5973; injectorvolume: 1 μL; initial column temperature: 50° C.; final columntemperature: 250° C.; ramp time: 20 minutes; gas flow rate: 1 mL/min;column: 5% phenyl methyl siloxane, Model No. HP 190915-443, dimensions:30.0 m×25 m×0.25 m).

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 300 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.Some compound samples were run at elevated temperatures (e.g., 75° C.)to promote increased sample solubility.

The purity of some of the compounds is assessed by elemental analysis(Desert Analytics, Tucson, Ariz.).

Melting points are determined on a Laboratory Devices MeI-Temp apparatus(Holliston, Mass.).

Preparative separations are carried out using a Flash 40 chromatographysystem and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flashcolumn chromatography using silica gel (230-400 mesh) packing material,or by HPLC using a Waters 2767 Sample Manager, C-18 reversed phasecolumn, 30×50 mm, flow 75 mL/min. Typical solvents employed for theFlash 40 Biotage system and flash column chromatography aredichloromethane, methanol, ethyl acetate, hexane, acetone, aqueousammonia (or ammonium hydroxide), and triethyl amine. Typical solventsemployed for the reverse phase HPLC are varying concentrations ofacetonitrile and water with 0.1% trifluoroacetic acid.

It should be understood that the organic compounds according to thepreferred embodiments may exhibit the phenomenon of tautomerism. As thechemical structures within this specification can only represent one ofthe possible tautomeric forms, it should be understood that thepreferred embodiments encompasses any tautomeric form of the drawnstructure.

It is understood that the invention is not limited to the embodimentsset forth herein for illustration, but embraces all such forms thereofas come within the scope of the above disclosure.

The examples below as well as throughout the application, the followingabbreviations have the following meanings. If not defined, the termshave their generally accepted meanings.

Abbreviations ACN Acetonitrile BINAP2,2′-bis(diphenylphosphino)-1,1′-binapthyl DCM Dichloromethane DIEAdiisopropylethylamine DIPEA N,N-diisopropylethylamine DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxideDPPF 1,1′-bis(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOHethanol HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HPLC high performance liquid chromatography MCPBAmeta-chloroperoxybenzoic acid MeOH methanol NBS N-bromosuccinimide NMPN-methyl-2-pyrrolidone RT room temperature THF tetrahydrofuran

Compounds of Formula I Example 1 Synthesis of4-[2-(2-Chloro-benzylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylicacid methylamide (Table 2, Compound 8)

Step 1. Synthesis of 2-Mercapto-benzooxazol-6-ol

To a solution of 4-aminoresorcinol (1 eq) and ethylxanthic acid (3 eq)in ethanol was added potassium hydroxide (2.1 eq). The mixture wasrefluxed for two hours then diluted with water and acidified using 1NHCl to a pH of 4. The product was extracted into ethyl acetate thenconcentrated. The resulting solid was triturated with dichloromethane togive pure product with a 90% yield. MH+=168.1.

Step 2. Synthesis of 2-Chloro-benzooxazol-6-ol

2-Mercapto-benzoxazol-6-ol (1 eq) was dissolved in thionyl chloride (10eq). DMF (0.6 eq) was slowly added to this solution at room temperature.The mixture was heated to 80° C. and refluxed for 15 minutes. Thereaction mixture was cooled to room temperature and the solvent wasremoved. The resulting solid was azeotroped three times with xylenes.The solid was dissolved in a 10% solution of THF in ethyl acetate andwashed once with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried with anhydrous sodium sulfate, filtered, and thesolvent removed. The solid was triturated with acetonitrile to yieldpure product with a 68% yield. MH+=170.0.

Step 3. Synthesis of 2-(2-Chloro-benzylamino)-benzooxazol-6-ol

2-Chloro-benzooxazol-6-ol (1 eq) and 2-chloro-benzylamine (2 eq) wasdissolved in NMP. Using a Personal Chemistry microwave system, themixture was reacted at 180° C. for six minutes. The crude reactionmixture was diluted with ethyl acetate and washed once with brine andonce with 1N HCl, or washed twice with brine, depending on the amineused. The organic layer was dried with anhydrous sodium sulfate,filtered and concentrated. This material was purified by silica gelcolumn using hexane and ethyl acetate. MH+=275.1.

Step 4. Synthesis of4-[2-(2-Chloro-benzylamino)-benzoxazol-6-yloxy]-pyridine-2-carboxylicacid methylamide

To a solution of 2-(2-chloro-benzylamino)-benzooxazol-6-ol (1 eq) inDMSO was added the 4-chloro-pyridine-2-carboxylic acid methylamide (1eq). This was allowed to stir for 15 minutes at room temperature atwhich point cesium carbonate (1.2 eq) was added. The solution was heatedin a Personal Chemistry microwave reactor at 150° C. for a total of 30minutes. The crude reaction mixture was diluted with ethyl acetate,washed three times with brine, dried over anhydrous sodium sulfate,filtered and concentrated. The crude product was then purified byreverse phase preparatory HPLC to give the pure product 8. MH+=409.1.

Compounds 9, 11, 12, 18, 19, 20, 26, 27, 28, and 40 in Table 2, below,were synthesized following similar procedures in Example 1.

Example 24-[2-((1S,2R)-2-Hydroxy-indan-1-ylamino)-benzoxazol-6-yloxy]-pyridine-2-carboxylicacid methylamide (Table 2, Compound 50)

Step 1. Synthesis of 2-(methylthio)benzo[d]oxazol-6-ol

To a solution of the 2-mercaptobenzo[d]oxazol-6-ol (1.55 g, 9.28 mmol,1.0 eq) in 20 mL of methylene chloride was added triethylamine (1.87 g,18.56 mmol, 2.0 eq) and methyl iodide (1.77 g, 13.92 mmol, 1.5 eq) atroom temperature. The reaction mixture was stirred at rt for 3 hours.The mixture was diluted with 100 mL of methylene chloride. The resultingmixture was washed with water (10 mL), brine (10 mL), then dried overMgSO₄, filtered, and evaporated under reduced pressure to give crudeproduct, which was purified by silica gel column eluted with ethylacetate and hexane to give the titled compound. MH+=182.

Step 2. Synthesis of4-(2-(methylthio)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide

To a solution of 2-(methylthio)benzo[d]oxazol-6-ol (8.5 g, 46.7 mmol, 1eq) in 80 mL of N,N-dimethylformamide was added4-chloro-N-methylpyridine-2-carboxamide (16.0 g, 93.4 mmol, 2.0 eq) andcesium carbonate (45.7 g, 140.1 mmol, 3.0 eq). The reaction mixture wasstirred at 75° C. for 6 hours. After the mixture was cooled to roomtemperature, the mixture was added 120 mL of water. After filtration,the solid was purified by silica gel column eluted with ethyl acetateand hexane to give the titled compound. MH+=316.

Step 3. Synthesis of4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide

To a solution of the4-(2-(methylthio)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide(1.26 g, 4.0 mmol, 1.0 eq) in 40 mL of methylene chloride was added3-chloroperoxybenzoic acid (70%, 989 mg, 4.4 mmol, 1.1 eq). The reactionmixture was stirred at room temperature for 5 hours and then was dilutedwith 200 mL of methylene chloride. The resulting mixture was washed withaqueous sodium bicarbonate and brine then dried over MgSO₄, filtered,and evaporated under reduced pressure to give crude product, which wasused to next step without further purification. MH+=332.

Step 4.4-[2-((1S,2R)-2-Hydroxy-indan-1-ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylicacid methylamide

A solution of4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide(17 mg, 0.05 mmol, 1.0 eq) and (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol(30 mg, 0.2 mml, 4.0 eq) in 1 mL of N,N-dimethylacetamide was heated inthe microwave at 90° C. for 600 seconds. The crude product was purifiedby reverse phase prep HPLC to give the title compound. MH==417.0.

Compounds 45, 46, and 47, in Table 2, below, were synthesized followingthe similar procedures as in Example 2 varying the temperature to 140°C. Compounds 42, 57, 59, and 94 in Table 2, below, were synthesizedfollowing the similar procedures as in Example 2 varying the temperatureto 120° C.

Example 3 Synthesis of1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]methyl}-cyclohexanecarboxylicacid ethyl ester (Table 2, Compound 75)

Step 1. Synthesis of 1-Cyano-cyclohexanecarboxylic acid ethyl ester

To a solution of cyanoacetate (1 eq) in DMF at 0° C. was slowly addedcesium carbonate (2.5 eq), followed by the slow addition of1,5-dibromopentane. This mixture was allowed to stir for 30 minutes at0° C. and at room temperature for two hours. The crude reaction mixturewas diluted with ethyl acetate and washed three times with water, driedwith anhydrous sodium sulfate, filtered, and concentrated. The compoundwas clean enough to continue without purification. 57% yield. ¹H NMR(300 MHz, CDCl₃) δ 4.25 (q, 2H), 2.12-1.68 (m, 10H), 1.31 (t, 3H).

Step 2. Synthesis of 1-Aminomethyl-cyclohexanecarboxylic acid ethylester

Excess Raney Nickel in an ethanol slurry was added to a solution of1-cyano-cyclohexanecarboxylic acid ethyl ester in ethanol under anitrogen atmosphere. The nitrogen atmosphere was replaced with excesshydrogen gas and the mixture was allowed to stir overnight. The reactionmixture was filtered through celite and the solvent was removed. Thecompound was clean enough to continue without purification. 80% yield.MH+=186.2.

Step 3. Synthesis of1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]methyl}-cyclohexanecarboxylicacid ethyl ester

To a solution of 1-aminomethyl-cyclohexanecarboxylic acid ethyl ester inTHF was added4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide from Step 3 of Example 2. After reacting at room temperaturefor 2 hours the solvent was removed and the crude product was dilutedwith ethyl acetate and some dichloromethane, then washed three timeswith brine, dried with anhydrous sodium sulfate, filtered andconcentrated. The final product was purified by reverse phasepreparatory HPLC. MH+=453.1.

Example 4 Synthesis of1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-methyl}-cyclohexanecarboxylicacid (Table 2, Compound 93)

1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]methyl}-cyclohexanecarboxylicacid ethyl ester (1 eq) was dissolved in 3 M sodium hydroxide (20 eq);THF and methanol were added to homogenize the solution. The mixture wasallowed to react at room temperature overnight. The solvents wereremoved. The crude product was brought to a pH of 4 with 1 N HCl, thento pH of 7 with saturated aqueous sodium bicarbonate. This solution wassaturated with solid sodium chloride then extracted three times withethyl acetate. The combined organic extracts were washed once withbrine, dried with anhydrous sodium sulfate, filtered and concentrated.The product was purified by silica gel column in isopropanol anddichloromethane (50%) MH+=425.1.

Example 5 Synthesis Of4-{2-[(1-Methylcarbamoyl-cyclohexylmethyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide (Table 2, Compound 112)

To a solution of1-{[6-(2-methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-methyl}-cyclohexanecarboxylicacid (1 eq) in DMF was added DIPEA (3 eq) and[dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluoro phosphate (1 eq). This was stirred at room temperature for 2hours, then a 2 M solution of methylamine in THF (5 eq) was added andallowed to react overnight at 70° C. The mixture was diluted with ethylacetate and washed twice with a saturated aqueous solution of ammoniumchloride and once with brine, then dried with anhydrous sodium sulfate,filtered and concentrated, then purified by preparatory reverse phaseHPLC. MH+=438.1.

Example 6 Synthesis of4-{2-[3-(2-Piperidin-1-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide (Table 2, Compound 44)

Step 1. Synthesis of Methanesulfonic acid 2-(3-nitro-phenyl)-ethyl ester

To a solution of 2-(3-nitro-phenyl)-ethanol (1 eq) in dichloromethane at0° C. was added pyridine (4 eq) and methanesulfonyl chloride (2 eq).After stirring at 0° C. for one hour, then room temperature overnight,the mixture was diluted with dichloromethane and washed once with water,once with 1 N HCl, dried with anhydrous sodium sulfate, filtered andconcentrated. The product was clean enough to be taken on to the nextstep without purification. MH+=246.0.

Step 2. Synthesis of 1-[2-(3-Nitro-phenyl)-ethyl]-piperidine

Methanesulfonic acid 2-(3-nitro-phenyl)-ethyl ester was dissolved inpiperidine (20 eq) and THF and stirred at 60° C. for one hour. Thesolvent was removed. The crude product was diluted with ethyl acetate,washed three times with water, dried with anhydrous sodium sulfate,filtered and concentrated. The product was clean enough to carry forwardwithout purification. 44% yield. MH+=235.1.

Step 3. Synthesis of 3-(2-Piperidin-1-yl-ethyl)-phenylamine

To a solution of 1-[2-(3-Nitro-phenyl)-ethyl]-piperidine in ethanol wasadded a catalytic amount 10% activated palladium on carbon and excesshydrogen gas. This mixture was allowed to stir overnight, then filteredand concentrated. The product was clean enough for the next reaction.60% yield. MH+=205.1.

Step 4. Synthesis of4-{2-[3-(2-Piperidin-1-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide

The 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide from step 3 of Example 2 and3-(2-piperidin-1-yl-ethyl)-phenylamine were dissolved in DMAC and heatedin a CEM microwave reactor at 120° C. for 10 to 20 minutes. The crudereaction mixture was purified by preparatory reverse phase HPLC.MH+=472.2.

Example 74-{2-[3-(2-Morpholin-4-yl-ethyl)-phenylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide (Table 2, Compound 74)

The compound Table 2, Entry 74 was synthesized following the similarprocedure as in Example 6. MH+=474.2.

Example 8 Synthesis of4-{2-[(2,3-Dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide (Table 2, Compound 110)

4-(2-Amino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide(1 eq) and 2,3-dihydro-1,4-benzodioxane-5-carboxylic acid (1 eq) weredissolved in DMF. To this solution were added DIPEA (3 eq) and[dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluoro phosphate (1 eq). The mixture was stirred at 40° C.overnight, then diluted with ethyl acetate and washed once each with 1NHCl, saturated aqueous sodium bicarbonate, and brine, and finally driedwith anhydrous sodium sulfate, filtered, and concentrated. This waspurified by preparatory reverse phase HPLC. MH+=447.0.

Example 9 Synthesis ofCyclohexylmethyl-[6-(2-[1,3,4]oxadiazol-2-yl-pyridin-4-yloxy)-benzooxazol-2-yl]-amine(Table 2, Compound 81)

Step 1. Synthesis of4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide

To a solution of4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide(1.40 g, 4.23 mmol, 1.0 eq) in 15 mL of THF was addedcyclohexylmethanamine (955 mg, 8.46 mmol, 2.0 eq) at room temperature.The reaction mixture was stirred at that temperature for 2 hours. Afterthe solvent was removed under reduced pressure, the residue wasdissolved in 150 mL of ethyl acetate. The resulting mixture was washedwith water (20 mL), brine (20 mL), then dried over MgSO₄, filtered, andevaporated under reduced pressure to give crude product, which waspurified by silica gel column eluted with ethyl acetate and hexane togive the titled compound. MH⁺=381.

Step 2. Synthesis of4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylicacid

A solution of4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide(300 mg, 0.79 mmol, 1.0 eq) in 10 mL of 10M aqueous hydrochloric acidsolution was stirred at 100° C. for 24 hours. The reaction mixture wascooled to room temperature. Most of water was removed under reducedpressure. And then aqueous sodium bicarbonate was added to the mixtureuntil pH>7.0. After filtration, the solid was washed with water anddried to give the titled compound. MH+=368.0.

Step 3. Synthesis of4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide

To a solution of the4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylicacid (110 mg, 0.30 mmol, 1.0 eq) in 2 mL of N,N-dimethylformamide wasadded benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (199 mg, 0.45 mmol, 1.5 eq), tert-butyl carbazate(47 mg, 0.36 mmol, 1.2 eq) and triethyl amine (60 mg, 0.60 mmol, 2.0 eq)at room temperature. The reaction mixture was stirred at thattemperature for 2 hours. Then the mixture was added 20 mL of water.After filtration, the solid was purified again by silica gel columneluted with ethyl acetate and hexane to give the Boc protected titledcompound.

The Boc protected titled compound (54 mg, 0.112 mmol, 1.0 eq) wasdissolved in 1 mL of methanol. And then the mixture was added 3 mL of 4Mhydrogen chloride in dioxane. The reaction mixture was stirred at roomtemperature overnight. The solvents were removed to give the titledcompound, which was used to next step without further purification.MH+=382.0.

Step 4. Synthesis ofcyclohexylmethyl-[6-(2-[1,3,4]oxadiazol-2-yl-pyridin-4-yloxy)-benzooxazol-2-yl]-amine

A solution of4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide(8 mg, 0.019 mmol, 1.0 eq) and 0.1 mL of 4 M hydrogen chloride in 1 mLtrimethyl orthoformate was heated in the microwave at 120° C. for 1200seconds. The crude product was purified by reverse phase prep HPLC togive the title compound. MH⁺=392.0

Compound 81 was also isolated from the reaction. MH+=367.0.

Example 10 Synthesis of4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carbonitrile(Table 2, Compound 82)

To a solution of the methylsulfoxide (32 mg, 0.41 mmol, 6.0 eq) in 1 mLof methylene chloride was added oxalyl chloride (2M, 0.135 mL, 0.27mmol, 4.0 eq) at −78° C. After 15 minutes, the4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carboxamide(25 mg, 0.068 mmol, 1.0 eq) in 2 mL of methylene chloride was added tothe reaction mixture. After being stirred at that temperature for 20minutes, triethyl amine (83 mg, 0.83 mmol, 12 eq) was added to mixture.The reaction mixture was stirred at −78° C. for 2 hours, and then wasquenched with aqueous ammonium chloride solution. The resulting mixturewas extracted with ethyl acetate (2×20 mL). The combined organic layerswere washed with water (5 mL), brine (5 mL), then dried over MgSO₄,filtered, and evaporated under reduced pressure to give crude product,which was purified by reverse phase prep HPLC to give the titlecompound. MH+=349.0.

Example 11 Synthesis of{4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridin-2-yl}-methanol(Table 2, Compound 80)

To a solution of the4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carboxylicacid (120 mg, 0.33 mmol, 1.0 eq) in 5 mL of THF was addedborane-tetrahydrofuran complex (1M, 1 mL, 1 mmol) at 0° C. The reactionmixture was stirred at that temperature for 5 hours. The reaction wasquenched with 1M hydrochloric acid. The resulting mixture was extractedwith ethyl acetate (2×60 mL). The combined organic layers were washedwith water (10 mL), brine (10 mL), then dried over MgSO₄, filtered, andevaporated under reduced pressure to give crude product, which waspurified by silica gel column eluted with ethyl acetate and hexane togive the titled compound. MH+=354.0.

Example 12 Synthesis ofCyclohexylmethyl-{6-[2-(5-methyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-benzooxazol-2-yl}-amine(Table 2, Compound 109)

Step 1. Synthesis of4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbaldehyde

To a solution of the4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methanol(20 mg, 0.057 mmol, 1.0 eq) in 2 mL of methylene chloride and 2 mL ofTHF was added Dess-Martin reagent (26 mg, 0.062 mmol, 1.1 eq) at roomtemperature. The reaction mixture was stirred at that temperature for 4hours. Then the mixture was diluted with 50 mL of ethyl acetate. Theresulting mixture was washed with aq sodium bicarbonate (5 mL), water (5mL), brine (5 mL), then dried over MgSO₄, filtered, and evaporated underreduced pressure to give crude product, which was purified bypreparative TLC sheet to give the titled compound. MH+=352.0.

Step 2. Synthesis ofCyclohexylmethyl-{6-[2-(5-methyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-benzooxazol-2-yl}-amine

To a solution of the4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbaldehyde(5 mg, 0.014 mmol, 1.0 eq) in 0.6 mL of methanol was added pyruvicaldehyde (40%, 0.1 mL) and 0.15 mL ammonium hydroxide at roomtemperature. The reaction mixture was stirred at that temperature for 2hours. The crude product was purified by reverse phase prep HPLC to givethe title compound. MH+=404.0.

Example 13 Synthesis of[6-(2-Aminomethyl-pyridin-4-yloxy)-benzooxazol-2-yl]-cyclohexylmethyl-amine(Table 2, Compound 111)

To a solution of the(4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methanol(20 mg, 0.057 mmol, 1.0 eq) in 2 mL of THF was added triphenyl phosphine(22 mg, 0.085 mmol, 1.5 eq), phthalimide (12.5 mg, 0.085 mmol, 1.5 eq)and diisopropyl azodicarboxylate (17 mg, 0.085 mmol, 1.5 eq) at roomtemperature. The reaction mixture was stirred at that temperature for 16hours. Then the solvent was removed. The crude product was purified bypreparative TLC sheet to give2-((4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methyl)isoindoline-1,3-dione.

The2-((4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methyl)isoindoline-1,3-dione(6.2 mg, 0.013 mmol, 1 eq) was dissolved in 0.5 mL of ethanol. And thenhydrazine monohydrate (6.4 mg, 0.13 mmol, 10 eq) was added to thereaction mixture. The mixture was stirred at room temperature for 3hours. And then the solvents were removed. The crude product waspurified by reverse phase prep HPLC to give the title compound.MH+=353.0.

Example 14 Synthesis of4-{2-[1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide (Table 2, Compound 125)

Step 1. Synthesis ofC-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine

To a suspension of amine bound on a rink resin (1 eq) intrimethylorthoformate was added2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde (2 eq). This mixture wasshaken overnight, filtered and the solid dried.

Step 2. Synthesis of 1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamine

The dried resin to which theC-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine (1 eq) was boundwas suspended in dry toluene. Under a nitrogen atmosphere methylmagnesium bromide (150 eq) in a 3 M solution in ethyl ether was added.This mixture was shaken for 24 hours at 60° C. then filtered and washedwith toluene, water, then methanol and dichloromethane alternately threetimes. The final wash was with methanol. The solid was dried undervacuum.

Step 3. Cleavage of 1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylaminefrom resin

To the resin bound 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylaminesuspended in dichloromethane was added trifluoroacetic acid (20% byvolume). The mixture was shaken overnight then the mixture was madebasic by the addition of 3 M sodium hydroxide. The solution was filteredto remove the resin, then diluted with dichloromethane and water. Thewater layer was extracted three times with dichloromethane. The combinedorganic extracts were washed once with brine, dried with anhydroussodium sulfate, filtered and concentrated. The material recovered wasclean enough to carry forward with no purification. MH+=180.1.

Step 4. Synthesis of4-{2-[1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylicacid methylamide

To a solution of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine (3 eq)in THF was added4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide (1 eq). This was stirred at room temperature for 8 hours,concentrated and the residue was purified by preparatory reverse phaseHPLC. MH+=447.1.

Compounds 41, 42, 57, 59, 65, 90, 94, 113, and 122 in Table 2, below,were synthesized following the similar procedures as in Example 14.

Example 15 Scheme 8 Preparation of4-[2-(Cyclohexylmethyl-amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylicacid methylamide (Table 2, Compound 128)

Step 1. Preparation of 2-Mercapto-benzothiazol-6-ol

As per the U.S. Pat. No. 4,873,346, hereby incorporated by reference inits entirety—Substituted Benzothiazoles, Benzimidazoles andbenzoxazoles; Anderson, David J.; The Upjohn Company, Kalamazoo, Mich.;Oct. 10, 1989. M+H=184.0

Step 2. Preparation of 2-Methylsulfanyl-benzothiazol-6-ol

To the ice cooled solution of 2-mercapto-benzothiazol-6-ol from step 1(3.80 g, 20.76 mmol, 1.0 eq) in DCM (40 mL, 0.5M) at 0° C., was addedtriethylamine (7.29 mL, 51.91 mmol, 2.5 eq) followed by iodomethane(1.93 mL, 31.14 mmol, 1.5 eq). The reaction was stirred from 0° C. to−10° C. for 3 hours. The solvent was removed in vacuo. Water (ca. 200mL) was added and the aqueous layer was extracted with ethyl acetate(3×150 mL). The organic layer was dried over sodium sulfate, filtered,and evaporated in vacuo to yield 2-methylsulfanyl-benzothiazol-6-ol aslight green powder (3.76 g, 92%). The crude product was used in the nextstep without purification. M+H=198.0

Step 3. Preparation of4-(2-Methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide

To the solution of 2-methylsulfanyl-benzothiazol-6-ol (3.76 g, 19.08mmol, 1.0 eq) in DMF (25 mL), was added CsCO₃ (15.54 g, 47.70 mmol, 2.5eq) at room temperature. After stirring for a while,4-chloro-pyridine-2-carboxylic acid methylamide (4.86 g, 28.62 mmol, 1.5eq) was added to the mixture and the mixture was stirred at 70° C. underreflux condenser overnight. After cooling the reaction mixture in icebath, water (100 mL) was added and the aqueous layer was extracted withethyl acetate (3×150 mL). The organic layer was dried over sodiumsulfate, filtered, and evaporated in vacuo. The crude product waspurified using 20 g of ISCO Silica Gel column (0%-50%-80%-100% ethylacetate-hexane mixture over 45 min 40 mL/min run) to yield4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide (3.88 g, 62%) as a white solid. M+H=332.1

Step 4. Preparation of4-(2-Methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide

To the solution of4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide from step 3 (3.88 g, 11.72 mmol, 1.0 eq) in DCM (20 mL) at0° C., was added MCPBA (77%, 2.88 g, 1. eq). The mixture was stirred atthis temperature for one hour. Saturated sodium bicarbonate solution(100 mL) was added. The aqueous layer was extracted with DCM (3×150 mL).The organic layer was dried over sodium sulfate, filtered, andevaporated in vacuo to yield4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide as white powder in quantitative yields. The crude productwas used in the next step without purification. M+H=348.0.

Step 5. Preparation of4-[2-(Cyclohexylmethyl-amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylicacid methylamide

To the solution of4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide (25 mg, 0.072 mmol, 1.0 eq) in DMF (500 μL), was addedcyclohexylmethylamine (18.7 μL, 0.144 mmol, 2.0 eq) and reaction wasstirred at 70° C. overnight. The neat reaction mixture was purified onreverse phase preparatory HPLC. Pure fractions were lyophilized as TFAsalts. M+H=397.1

Example 16 Preparation of4-(2-((1S,2S)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(Table 2, Compound 137)

To the solution of4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acidmethylamide (70 mg, 0.202 mmol, 1.0 eq) in DMA (600 μL), was added(1S,2S)-2-aminocyclohexanol hydrochloride (92 mg, 0.606 mmol, 3.0 eq)followed by diisopropylethylamine (0.21 mL, 1.21 mmol). The reaction washeated at 110° C. for 24-hours. The neat reaction mixture was purifiedon reverse phase preparatory HPLC. Pure fractions were lyophilized asTFA salts. M+H=398

Example 17

The compounds in the following Table 2 were made by the generalprocedures described above.

TABLE 2 Com- M + H; pound Structure Rt (min) Compound Name 1

440.2; 5.1 4-[2-(4-Bromo- phenylamino)-benzooxazol- 6-yloxy]-pyridine-2-carboxylic acid methylamide 2

389.2 4-[2-((R)-1-Phenyl- ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 3

446.1; 2.74 4-[2-(2-Morpholin-4-yl- phenylamino)-benzooxazol-6-yloxy]-pyridin-2- carboxylic acid methylamide 4

472.1; 2.46 (2,3-Dihydro- benzo[1,4]dioxin-6-yl)-[6-(6,7-dimethoxy-quinolin-4- yloxy)-benzooxazol-2-yl]- amine 5

419.1; 2.53 4-[2-(2,3-Dihydro-benzo- [1,4]dioxin-6-ylamino)-benzooxazol-6-yloxy]- pyridin-2-carboxylic acid methylamide 6

396.1; 2.07 4-[2-(1-Thiazol-2-yl- ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 7

389.2; 2.48 4-[2-((S)-1-Phenyl- ethylamino)-benzooxazol-6-yloxy]-pyridin-2-carboxylic acid methylamide 8

409.1; 2.62 4-[2-(2-Chloro- benzylamino)-benzooxazol-6-yloxy]-pyridin-2- carboxylic acid methylamide 9

443.0; 2.92 4-[2-(2,4-Dichloro- benzylamino)-benzooxazol-6-yloxy]-pyridin-2- carboxylic acid methylamide 10

381.1; 2.53 4-[2-(3-Methyl-cyclohexyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 11

391.1; 2.77 4-[2-(2-Methoxy- phenylamino)-benzooxazol-6-yloxy]-pyridin-2- carboxylic acid methylamide 12

405.2; 2.98 4-[2-(2-Ethoxy- phenylamino)-benzooxazol-6-yloxy]-pyridin-2- carboxylic acid methylamide 13

421.2; 2.98 4-[2-((1S,2S,3S,5R)-2,6,6- Trimethyl- bicyclo[3.1.1]hept-3-ylamino)-benzooxazol-6- yloxy]-pyridin-2-carboxylic acid methylamide 14

442.2; 2.50 [6-(6,7-Dimethoxy-quinolin- 4-yloxy)-benzooxazol-2-yl]-((R)-1-phenyl-ethyl)-amine 15

421.3; 2.96 4-{2-[((1S,2R,4R)-7,7- Dimethyl-bicyclo[2.2.1]hept-2-ylmethyl)-amino]- benzooxazol-6-yloxy}- pyridin-2-carboxylic acidmethylamide 16

393.0; 2.46 4-[2-(2-Fluoro- benzylamino)-benzooxazol-6-yloxy]-pyridin-2- carboxylic acid methylamide 17

405.1; 2.44 4-[2-(2-Methoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 18

439.1; 2.83 4-[2-((R)-1-Naphthalen-1-yl- ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 19

403.1; 2.62 4-[2-((R)-1-Phenyl-propyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 20

439.2; 2.83 4-[2-((S)-1-Naphthalen-2-yl- ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 21

381.1; 2.55 4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 22

339.0; 2.09 4-(2-Cyclobutylamino- benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 23

353.1; 2.18 4-(2-Cyclopentylamino- benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 24

367.1; 2.33 4-(2-Cyclohexylamino- benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 25

460.1; 2.02 4-[2-(2-Morpholin-4- ylmethyl-phenylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 26

361.0; 2.61 4-(2-Phenylamino- benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 27

409.0; 2.61 4-[2-(4-Chloro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 28

421.0; 2.57 4-[2-(2,4-Dimethoxy-phenyl- amino)-benzooxazol-6-yl-oxy]-pyridine-2-carboxylic acid methylamide 29

367.0; 2.11 N-[4-(2-Cyclohexylamino- benzooxazol-6-yloxy)-pyridin-2-yl]-acetamide 30

369.1; 1.90 4-[2-(Tetrahydro-pyran-4-yl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 31

419.0; 2.55 4-{2-[(R)-1-(2-Methoxy- phenyl)-ethylamino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 32

409.1; 2.31 N-{4-[2-(2-Chloro- benzylamino)-benzooxazol-6-yloxy]-pyridin-2-yl}- acetamide 33

411.0; 2.53 4-[2-(2,5-Difluoro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 34

381.1; 2.33 N-{4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridin-2-yl}- acetamide 35

419.1; 2.26 (R)-[6-(2-Methylcarbamoyl- pyridin-4-yloxy)-benzooxazol-2-ylamino]- phenyl-acetic acid 36

432.1; 2.16 4-{2-[((R)- Methylcarbamoyl-phenyl- methyl)-amino]-benzo-oxazol-6-yloxy}-pyridine-2- carboxylic acid methylamide 37

405.1; 2.07 4-[2-((R)-2-Hydroxy-1- phenyl-ethylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 38

419.1; 2.26 (S)-[6-(2-Methylcarbamoyl- pyridin-4-yloxy)-benzooxazol-2-ylamino]- phenyl-acetic acid 39

432.1; 2.16 4-{2-[((S)-Methylcarbamoyl- phenyl-methyl)-amino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 40

376.1; 1.76 4-{2-[(Pyridin-2-ylmethyl)- amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide 41

375.1; 2.38 4-(2-Benzylamino- benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 42

409.0; 2.62 4-[2-(3-Chloro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 43

458.2; 2.13 4-{2-[2-(2-Pyrrolidin-1-yl- ethyl)-phenylamino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 44

472.2; 2.16 4-{2-[2-(2-Piperidin-1-yl- ethyl)-phenylamino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 45

441.0; 2.16 4-{2-[2-(4-Methyl-imidazol- 1-yl)-phenylamino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 46

428.1; 2.42 4-[2-(2-Oxazol-5-yl- phenylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 47

441.2; 2.29 4-{2-[2-(2-Methyl-imidazol- 1-yl)-phenylamino]-benzooxazol-6-yloxy}- pyridine-2- carboxylic acid methylamide 48

474.1; 2.09 4-{2-[2-(2-Morpholin-4-yl- ethyl)-phenylamino]-benzo-oxazol-6-yloxy}-pyridine-2- carboxylic acid methylamide 49

417.0; 2.05 4-[2-((1S,2R)-2-Hydroxy- indan-1-ylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 50

417.0; 2.05 4-[2-((1R,2S)-2-Hydroxy- indan-1-ylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 51

419.0; 2.18 4-[2-((R)-3-Hydroxy-1- phenyl-propylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 52

383.0; 1.94 4-[2-((1S,2S)-2-Hydroxy- cyclohexylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 53

433.0; 2.51 (R)-[6-(2-Methylcarbamoyl- pyridin-4-yloxy)-benzooxazol-2-ylamino]- phenyl-acetic acid methyl ester 54

395.1; 2.68 4-[2-((R)-1-Cyclohexyl- ethylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 55

433.0; 2.53 (S)-[6-(2-Methylcarbamoyl- pyridin-4-yloxy)-benzooxazol-2-ylamino]- phenyl-acetic acid methyl ester 56

405.0; 2.01 4-[2-((S)-2-Hydroxy-1- phenyl-ethylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 57

376.1; 1.72 4-{2-[(Pyridin-4-ylmethyl)- amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide 58

472.1; 2.16 4-{2-[3-(2-Piperidin-1-yl- ethyl)-phenylamino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 59

376.1; 1.76 4-{2-[(Pyridin-3-ylmethyl)- amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide 60

368.0; 2.13 4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid 61

389.1; 2.40 4-(2-Phenylethylamino-benzo- oxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 62

438.0; 2.33 4-{2-[((R)-Cyclohexyl- methylcarbamoyl-methyl)-amino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 63

382.2; 1.74 4-[2-(2-Pyrrolidin-1-yl- ethylamino)-benzooxazol-6-yloxy]-pyridin-2-carboxylic acid methylamide 64

396.2; 1.83 4-[2-(2-Piperidin-1-yl-ethyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 65

433.0; 2.40 4-{2-[(2,3-Dihydro-benzo- [1,4]dioxin-5-ylmethyl)-amino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 66

411.1; 2.31 4-[2-((S)-1-Cyclohexyl-02- hydroxy-ethylamino)-benzo-oxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 67

411.1; 2.33 4-[2-((R)-1-Cyclohexyl-2- hydroxy-ethylamino)-benzo-oxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 68

482.1; 2.92 N'-{4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carbonyl}- hydrazinecarboxylic acid tert-butyl ester69

367.1; 2.46 4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid amide 70

365.1; 2.29 4-[2-(Cyclohex-3- enylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 71

411.1; 2.53 4-[2-(2,4-Difluoro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 72

455.0; 2.66 4-[2-(2-Bromo- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 73

423.0; 2.48 4-[2-(2-Fluoro-5-methoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 74

474.2; 2.03 4-{2-[3-(2-Morpholin-4-yl- ethyl)-phenylamino]-benzo-oxazol-6-yloxy}-pyridine-2- carboxylic acid methylamide 75

453.1; 2.79 1-{[6-(2-Methylcarbamoyl- pyridin-4-yloxy)-benzooxazol-2-ylamino]- methyl}-cyclohexane- carboxylic acid ethyl ester76

443.0; 2.72 4-[2-(2,6-Dichloro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 77

443.0; 2.83 4-[2-(2,3-Dichloro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 78

427.0; 2.59 4-[2-(2-Chloro-6-fluoro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 79

411.1; 2.53 4-[2-(2,3-Difluoro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 80

354.1; 2.22 {4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridin-2-yl}- methanol 81

392.1; 2.59 Cyclohexylmethyl-[6-(2- [1,3,4]oxadiazol-2-yl-pyridin-4-yloxy)- benzooxazol-2-yl]-amine 82

349.1; 2.93 4-[2-(Cyclohexylmethyl- amino)-benzooxazol-6-yloxy]-pyridine-2- carbonitrile 83

435.1; 2.46 4-[2-(2,5-Dimethoxy-benzyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 84

435.1; 2.44 4-[2-(2,6-Dimethoxy-benzyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 85

419.1; 2.55 4-[2-(2-Dimethylamino- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 86

390.1; 1.98 4-[2-(2-Amino- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 87

411.1; 2.48 4-[2-(2,6-Difluoro- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 88

460.1; 2.40 4-[2-(2-Morpholin-4-yl- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 89

389.1; 2.53 4-[2-(2-Methyl- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 90

435.1; 2.29 4-[2-(3,4-Dimethoxy-benzyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 91

435.1; 2.42 4-[2-(2,3-Dimethoxy-benzyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 92

435.1; 2.44 4-[2-(2,4-Dimethoxy-benzyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 93

425.1; 2.29 1-{[6-(2-Methylcarbamoyl- pyridin-4-yloxy)-benzooxazol-2-ylamino]- methyl}-cyclohexane- carboxylic acid 94

419.1; 2.62 4-[2-(2,3-Dihydro-benzo- [1,4]dioxin-5-ylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 95

405.0; 2.57 4-[2-(Benzo[1,3]dioxol-5-yl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 96

419.1; 2.62 4-[2-(2-Ethoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 97

443.1; 2.77 4-[2-(2-Trifluoromethyl- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 98

327.1; 1.94 4-(2-Isopropylamino-benzo- oxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 99

341.1; 2.18 4-(2-Isobutylamino- benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 100

341.1; 2.24 4-(2-tert-Butylamino-benzo- oxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 101

395.2; 2.74 4-[2-(Cycloheptylmethyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 102

369.1; 1.98 4-{2-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 103

458.1; 2.05 4-[2-(1-Benzyl-piperidin-4- ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 104

415.1; 2.70 4-[2-(1,2,3,4-Tetrahydro- naphthalen-1-ylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 105

441.1; 2.40 4-[2-(2-Pyrazol-1-yl-benzyl- amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 106

389.1; 2.66 4-[2-(Benzyl-methyl-amino)- benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 107

444.1; 2.02 4-[2-(1-Phenyl-piperidin-4- ylamino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 108

447.1; 2.42 4-{2-[(3,4-Dihydro-2H- benzo[b][1,4]dioxepin-6-ylmethyl)-amino]- benzooxazol-6-yloxy}- pyridine-2-carboxylic acidmethylamide 109

404.1; 2.38 Cyclohexylmethyl-{6-[2-(5- methyl-1H-imidazol-2-yl)-pyridin-4-yloxy]- benzooxazol-2-yl}-amine 110

447.0; 2.42 4-{2-[(2,3-Dihydro-benzo- [1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 111

353.1; 2.18 [6-(2-Aminomethyl-pyridin- 4-yloxy)-benzooxazol-2-yl]-cyclohexylmethyl-amine 112

438.1; 2.16 4-{2-[(1-Methylcarbamoyl- cyclohexylmethyl)-amino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 113

465.1; 2.46 4-[2-(2,4,6-Trimethoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 114

439.1; 2.68 4-[2-(5-Chloro-2-methoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 115

423.1; 2.53 4-[2-(5-Fluoro-2-methoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 116

423.1; 2.48 4-[2-(2-Fluoro-6-methoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 117

469.1; 2.57 4-[2-(2-Chloro-3,4- dimethoxy-benzylamino)-benzooxazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 118

458.1; 2.20 4-[2-(2-Piperidin-1-yl- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 119

433.1; 2.55 4-{2-[(2,3-Dihydro-benzo- [1,4]dioxin-2-ylmethyl)-amino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 120

474.1; 2.01 4-{2-[(4-Benzyl-morpholin- 2-ylmethyl)-amino]-benzooxazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 121

439.0; 2.63 4-[2-(2-Chloro-6-methoxy- benzylamino)-benzooxazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 122

433.1; 2.37 4-{2-[(2,3-Dihydro-benzo- [1,4]dioxin-6-ylmethyl)-amino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 123

447.1; 2.44 4-{2-[2-(2,3-Dihydro-benzo- [1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide124

417.1; 2.37 4-{2-[(2,3-Dihydro- benzofuran-5-ylmethyl)-amino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 125

447.1; 2.50 4-{2-[1-(2,3-Dihydro-benzo- [1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6- yloxy}-pyridine-2-carboxylic acid methylamide126

479.9; 5.1 4-[2-(4-Chloro-3- trifluoromethyl- phenylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 127

425.0; 2.57 4-[2-(2-Chloro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 128

397.1; 2.48 4-[2-(Cyclohexylmethyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 129

435.1; 2.48 4-{2-[(R)-1-(2-Methoxy- phenyl)-ethylamino]-benzothiazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 130

459.0; 2.88 4-[2-(2,4-Dichloro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 131

405.1; 2.42 4-[2-((R)-1-Phenyl- ethylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 132

421.1; 2.37 4-[2-(2-Methoxy- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 133

405.0; 2.35 4-(2-Phenethylamino-benzo- thiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 134

458.9; 2.81 4-[2-(2,3-Dichloro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 135

383.1; 2.27 4-(2-Cyclohexylamino- benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide 136

397.1; 2.46 4-[2-(3-Methyl-cyclohexyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 137

399.1; 1.94 4-[2-((1S,2S)-2-Hydroxy- cyclohexylamino)-benzothiazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 138

411.1; 2.59 4-[2-((R)-1-Cyclohexyl- ethylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 139

427.0; 2.53 4-[2-(2,5-Difluoro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 140

409.0; 2.40 4-[2-(2-Fluoro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 141

399.1; 1.94 4-{2-[(tetrahydro-pyran-4- ylmethyl)-amino]-benzothiazol-6-yloxy}- pyridine-2-carboxylic acid methylamide 142

476.1; 2.38 4-[2-(2-Morpholin-4-yl- benzylamino)-benzothiazol-6-yloxy]-2-pyridine-2- carboxylic acid methylamide 143

457.1; 2.33 4-[2-(2-Pyrazol-1-yl-benzyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 144

434.1; 2.05 4-[2-(2-Dimethylamino- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 145

451.1; 2.38 4-[2-(2,6-Dimethoxy-benzyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 146

451.1; 2.39 4-[2-(2,5-Dimethoxy-benzyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 147

427.0; 2.53 4-[2-(2,3-Difluoro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 148

411.1; 2.62 4-[2-(Cycloheptylmethyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 149

427.0; 2.46 4-[2-(2,6-Difluoro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 150

392.1; 1.83 4-{2-[(Pyridin-2-ylmethyl)- amino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic acid methylamide 151

451.0; 2.22 4-[2-(3,4-Dimethoxy-benzyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide 152

449.0; 2.35 4-{2-[(2,3-Dihydro-benzo- [1,4]dioxin-5-ylmethyl)-amino]-benzothiazol-6- yloxy}-pyridine-2-carboxylic acid methylamide 153

474.1; 2.31 4-[2-(2-Piperidin-1-yl- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 154

392.0; 1.78 4-{2-[(Pyridin-3-ylmethyl)- amino]-benzothiazol-6-yloxy}-pyridine-2-carboxylic acid methylamide 155

489.2; 2.57 4-[2-((1R,2R)-2-Benzyloxy- cyclohexylamino)-benzothiazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 156

489.1; 2.57 4-[2-((1S,2S)-2-Benzyloxy- cyclohexylamino)-benzothiazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 157

399.1; 1.94 4-[2-((1R,2R)-2-Hydroxy- cyclohexylamino)-benzothiazol-6-yloxy]- pyridine-2-carboxylic acid methylamide 158

459.0; 2.68 4-[2-(2,6-Dichloro- benzylamino)-benzothiazol-6-yloxy]-pyridine-2- carboxylic acid methylamide 159

441.1; 2.59 4-(2-(cyclohexylmethyl- amino)benzothiazol-6-yloxy)-N-(2-methox.ylethyl)- pyridine-2-carboxamide 160

454.2; 2.26 4-(2-(cyclohexylmethyl- amino)benzothiazol-6- yloxy)-N-(2-(dimethylamino)- ethyl)pyridine-2- carboxamide 161

470.0; 2.00 4-[2-(4-Sulfonamido-benzyl- amino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide

Example 162 Preparation of4-(2-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (300mg, 0.86 mmol) in 5 ml of NMP was added(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (597 mg, 4 mmol) and DIPEA(300 μL, 1.73 mmol). The reaction solution was stirred at 105° C. for 24hours. The crude reaction solution was purified on prep HPLC andevaporated in vacuo to give4-(2-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(347 mg, 0.63 mmol) as TFA salt. ES/MS m/z 433.1 (MH⁺).

Example 163 Preparation of4-(2-((1R,2R)-2-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15mg, 43 μmole) in 400 μL of NMP was added (1R,2R)-cyclohexane-1,2-diamine(17 mg, 150 μmole). The reaction solution was stirred at 105° C. for 24hours. The crude reaction solution was purified on prep HPLC andevaporated in vacuo to give4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(12 mg, 30 μmole) as white powder. ES/MS m/z 398.1 (MH⁺).

Step 2. Preparation of4-(2-((1R,2R)-2-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(9 mg, 22 μmole) and triethylamine (11 μL, 80 μmole) in 300 μL of DMFwas added acetic anhydride (5 μL, 50 μmole). The reaction solution wasstirred at room temperature for 1.5 hours. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give4-(2-((1R,2R)-2-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(5.1 mg, 12 μmole) as white powder. ES/MS m/z 440.2 (MH⁺).

Example 164 Preparation of(S)—N-methyl-4-(2-(1-(methylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (104mg, 0.3 mmol) in 2 ml of NMP was added (S)-tert-butyl3-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol). The reactionsolution was stirred at 105° C. for 5 days. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) as white powder. ES/MS m/z 484.2 (MH⁺).

Step 2. Preparation of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

(S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) was dissolved in 4 ml of 4M HCl in dioxane (16 mmol).The reaction solution was stirred at room temperature for 1 hour. Thecrude reaction solution was evaporated in vacuo to give(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(46 mg, 0.12 mmol) as white solid. ES/MS m/z 384.0 (MH⁺).

Step 3. Preparation of(S)—N-methyl-4-(2-(1-(methylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

To the solution of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamidehydrochloride (12.5 mg, 30 μmol) and DIPEA (28 μL, 160 μmol) in 300 μLof NMP was added methanesulfonic anhydride (17 mg, 100 μmol). Thereaction solution was stirred at 105° C. for 46 hours. The crudereaction solution was purified on prep HPLC and evaporated in vacuo togive(S)—N-methyl-4-(2-(1-(methylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(4.5 mg, 9.8 μmol) as white powder. ES/MS m/z 462.1 (MH⁺).

Example 165 Preparation of(S)-4-(2-(1-acetylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (104mg, 0.3 mmol) in 2 ml of NMP was added (S)-tert-butyl3-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol). The reactionsolution was stirred at 105° C. for 5 days. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) as white powder. ES/MS m/z 484.2 (MH⁺).

Step 2. Preparation of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

(S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) was dissolved in 4 ml of 4M HCl in dioxane (16 mmol).The reaction solution was stirred at room temperature for 1 hour. Thecrude reaction solution was evaporated in vacuo to give(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(46 mg, 0.12 mmol) as white solid. ES/MS m/z 384.0 (MH⁺).

Step 3. Preparation of(S)-4-(2-(1-acetylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(13 mg, 30 μmol) and triethylamine (13 μL, 90 μmol) in 300 μL of DMA wasadded acetic anhydride (6 μl, 60 μmol). The reaction solution wasstirred at room temperature for 1.5 hours. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give(S)-4-(2-(1-acetylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(4.8 mg, 11 μmol) as white powder. ES/MS m/z 426.2 (MH⁺).

Example 166 Preparation of(S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (104mg, 0.3 mmol) in 2 ml of NMP was added (S)-tert-butyl3-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol). The reactionsolution was stirred at 105° C. for 5 days. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) as white powder. ES/MS m/z 484.2 (MH⁺).

Step 2. Preparation of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

(S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) was dissolved in 4 ml of 4M HCl in dioxane (16 mmol).The reaction solution was stirred at room temperature for 1 hour. Thecrude reaction solution was evaporated in vacuo to give(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(46 mg, 0.12 mmol) as white solid. ES/MS m/z 384.0 (MH⁺).

Step 3. Preparation of(S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the reaction solution of isobutyric acid (4 μl, 40 μmol), HATU (15mg, 40 μmol) and DIEA (14 μL, 80 μmol) in 400 μL of DMA was added(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(13 mg, 30 μmol) and DIPEA (6 μL, 30 μmol). The reaction solution wasstirred at room temperature for 16 hours. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give(S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(6.8 mg, 15 μmol) as white powder. ES/MS m/z 454.2 (MH⁺).

Example 167 Preparation of(S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (104mg, 0.3 mmol) in 2 ml of NMP was added (S)-tert-butyl3-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol). The reactionsolution was stirred at 105° C. for 5 days. The crude reaction solutionwas purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) as white powder. ES/MS m/z 484.2 (MH⁺).

Step 2. Preparation of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

(S)-tert-butyl3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(56 mg, 0.12 mmol) was dissolved in 4 ml of 4M HCl in dioxane (16 mmol).The reaction solution was stirred at room temperature for 1 hour. Thecrude reaction solution was evaporated in vacuo to give(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(46 mg, 0.12 mmol) as white solid. ES/MS m/z 384.0 (MH⁺).

Step 3. Preparation of(S)-4-(2-(1-(isopropylcarbamoyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide(13 mg, 30 μmol) and DIPEA (17 μL, 100 μmol) in 300 μL of NMP was added2-isocyanatopropane (5 μL, 50 μmol). The reaction solution was stirredat room temperature for 18 hours. The crude reaction solution waspurified on prep HPLC and evaporated in vacuo to give(S)-4-(2-(1-(isopropylcarbamoyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(5.9 mg, 12 μmol) as white powder. ES/MS m/z 469.2 (MH⁺).

Example 168 Preparation of(R)-4-methyl-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)pentan-1-ol

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole

To the mixture of 2-(methylthio)benzo[d]thiazol-6-ol (1 g, 5.08 mmol)and cesium carbonate (4.55 g, 14 mmol) in 15 ml of NMP was added2-chloro-4-fluoropyridine (1.32 mg, 10 mmol). The reaction mixture wasstirred at 55° C. for overnight. The reaction mixture was poured into 80ml of aq. saturated NaHCO₃ and extracted with ethyl acetate (2×150 ml).The combined organic layers were washed with aq. 0.1M NaHSO₄ (60 ml),water (2×60 ml) and brine (60 ml), then dried over MgSO₄, filtered andevaporated in vacuo to give6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole (1.72 g) asbrown oil that carried on to next step without purification. ES/MS m/z308.9 (MH⁺).

Step 2. Preparation of6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole

To the solution of6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole (1.72 g, 5.08mmol) in 32 ml of DCM was added 3-chloroperbenzoic acid (77%, 1.3 g, 5mmol) portion-wise at 0° C. After being stirred at room temperature for2 hours, the mixture was diluted with 80 ml of DCM. The resultingmixture was washed with aq. 0.2M Na₂S₂O₃ (25 ml), aq. saturated NaHCO₃(25 ml), water (25 ml) and brine, then dried over Na₂SO₄, filtered andevaporated in vacuo to give a yellow brown solid (1.72 g). The residuewas purified by flash column chromatography and evaporated in vacuo togive 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (970mg, 3 mmol) as ivory powder. ES/MS m/z 325.0 (MH⁺).

Step 3. Preparation of(R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol

To the solution of6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (26 mg,80 μmol) in 400 μL of NMP was added (R)-2-amino-4-methylpentan-1-ol (33μL, 250 μmol) and DIPEA (17 μL, 100 μmol). The reaction solution wasstirred at 100° C. for 18 hours. The crude reaction solution waspurified on prep HPLC and evaporated in vacuo to give(R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol(12 mg, 31 μmol) as powder. ES/MS m/z 378.1 (MH⁺).

Step 4. Preparation of(R)-4-methyl-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)pentan-1-ol

To the reaction mixture of(R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol(12 mg, 31 μmol) in 400 μL of DME,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21mg, 100 μmol), Pd(dppf)₂Cl₂ (7 mg, 8 μmol) and aq. 2M Na₂CO₃ (100 μL,200 μmol) were added. The reaction mixture was stirred at 90° C. for 24hours. The reaction mixture filtered, purified on prep HPLC andevaporated in vacuo to give(R)-4-methyl-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)pentan-1-olas powder (4.2 mg). ES/MS m/z 424.1 (MH⁺).

Example 169 Preparation of(S)—N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole

To the mixture of 2-(methylthio)benzo[d]thiazol-6-ol (1 g, 5.08 mmol)and cesium carbonate (4.55 g, 14 mmol) in 15 ml of NMP was added2-chloro-4-fluoropyridine (1.32 mg, 10 mmol). The reaction mixture wasstirred at 55° C. for overnight. The reaction mixture was poured into 80ml of aq. saturated NaHCO₃ and extracted with ethyl acetate (2×150 ml).The combined organic layers were washed with aq. 0.1M NaHSO₄ (60 ml),water (2×60 ml) and brine (60 ml), then dried over MgSO₄, filtered andevaporated in vacuo to give6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole (1.72 g) asbrown oil that carried on to next step without purification. ES/MS m/z308.9 (MH⁺).

Step 2. Preparation of6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole

To the solution of6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole (1.72 g, 5.08mmol) in 32 ml of DCM was added 3-chloroperbenzoic acid (77%, 1.3 g, 5mmol) portion-wise at 0° C. After being stirred at room temperature for2 hours, the mixture was diluted with 80 ml of DCM. The resultingmixture was washed with aq. 0.2M Na₂S₂O₃ (25 ml), aq. saturated NaHCO₃(25 ml), water (25 ml) and brine, then dried over Na₂SO₄, filtered andevaporated in vacuo to give a yellow brown solid (1.72 g). The residuewas purified by flash column chromatography and evaporated in vacuo togive 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (970mg, 3 mmol) as ivory powder. ES/MS m/z 325.0 (MH⁺).

Step 3. Preparation of (S)-tert-butyl3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the solution of6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (100 mg,0.31 mmol) in 1.6 ml of NMP was added (S)-tert-butyl3-aminopiperidine-1-carboxylate (200 mg, 1 mmol) and DIPEA (70 μL, 0.4mmol). The reaction solution was stirred at 95° C. for 5 days. The crudereaction solution was purified on prep HPLC and evaporated in vacuo togive (S)-tert-butyl3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(160 mg) as TFA salt. ES/MS m/z 461.1 (MH⁺).

Step 4. Preparation of (S)-tert-butyl3-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the reaction mixture of (S)-tert-butyl3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(68 mg, 148 μmol) in 1.2 m of DME,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40mg, 192 μmol), Pd(dppf)₂Cl₂ (18 mg, 22 μmol) and aq. 2M Na₂CO₃ (400 μL,800 μmol) were added. The reaction mixture was stirred at 85° C. for 72hours or until done by LC. The reaction mixture was poured into 40 ml ofsaturated NaHCO₃ solution and extracted with ethyl acetate (2×80 ml).The combined organic layers were washed with water (2×20 ml) and brine(20 ml), then dried over Na₂SO₄, filtered and evaporated in vacuo togive a brown glue (77 mg) that was purified on prep HPLC to give(S)-tert-butyl3-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylateas powder (9.6 mg). ES/MS m/z 507.1 (MH⁺).

Step 5. Preparation of(S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide

(S)-tert-butyl3-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate(9.6 mg, 19 μmol) was dissolved in 1 ml of 4M HCl in dioxane (4 mmol).The reaction solution was stirred at room temperature for 1 hour. Thecrude reaction solution was evaporated in vacuo to give(S)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-N-(piperidin-3-yl)benzo[d]thiazol-2-amine(7.6 mg, 18 μmol) as white solid. ES/MS m/z 407.1 (MH⁺).

Step 6. Preparation of(S)—N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

To the solution of(S)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-N-(piperidin-3-yl)benzo[d]thiazol-2-amine(7.6 mg, 18 μmol) and DIPEA (35 μL, 200 μmol) in 400 μL of NMP was addedcyclopropanesulfonyl chloride (10 mg, 98 μmol). The reaction solutionwas stirred at 55 for 16 hours. The crude reaction solution was purifiedon prep HPLC and evaporated in vacuo to give(S)—N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine(6.2 mg, 12 μmol) as white powder. ES/MS m/z 511.2 (MH⁺).

Example 170 Preparation ofN-(cyclohexylmethyl)-6-(2-(ethylamino)pyridin-4-yloxy)benzo[d]thiazol-2-amine

To the reaction solution of6-(2-chloropyridin-4-yloxy)-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine(12 mg, 0.03 mmol) in 400 μL of NMP was added DIPEA (9 μL, 0.05 mmol)and 70% ethylamine in water (200 μL, 2.51 mmol). The reaction mixturewas stirred at 110° C. for 96 hours or until done by LC. The crudereaction mixture was filtered, purified on prep HPLC and evaporated invacuo to giveN-(cyclohexylmethyl)-6-(2-(ethylamino)pyridin-4-yloxy)benzo[d]thiazol-2-amineas TFA salt (1.8 mg). ES/MS m/z 383.1 (MH⁺).

Example 171N-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Synthesis of tert-butyl4-(2-(methylthio)benzo[d]thiazol-6-yloxy)picolinate

To a solution of 2-(methylthio)benzo[d]thiazol-6-ol (5.0 g, 25.38 mmol,1.0 eq) in 25 mL of N,N-dimethylformamide was added tert-butyl4-chloropicolinate (8.13 g, 38.07 mmol, 1.5 eq) and cesium carbonate(20.67 g, 63.45 mmol, 2.5 eq). The reaction mixture was stirred at 75°C. for 6 hours. After the mixture was cooled to room temperature, themixture was added 120 mL of water and aqueous phase extracted with ethylacetate (3×150 mL), combined organic layers were dried over sodiumsulfate. After filtration, the solid was purified by silica gel columneluted with ethyl acetate-hexane 0%-50% mixture to give 5.84 g of thetitled compound as brown powder (62%). MH+=375.

Step 2. Synthesis of tert-butyl4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy) picolinate

To a solution of the tert-butyl4-(2-(methylthio)benzo[d]thiazol-6-yloxy)picolinate (5.84 g, 15.61 mmol,1.0 eq) in 25 mL of methylene chloride was added 3-chloroperoxybenzoicacid (77%, 3.84 g, 17.17 mmol, 1.1 eq). The reaction mixture was stirredat room temperature for 1.5 hours and then was diluted with 200 mL ofmethylene chloride. The resulting mixture was washed with aqueous sodiumbicarbonate and brine then dried over MgSO₄, filtered, and evaporatedunder reduced pressure to give crude product, which was used to nextstep without further purification. MH+=391.0.

Step 3. Preparation of tert-butyl 4-(2-((1R,2R)-2hydroxycyclohexylamino)-benzo[d]thiazol-6-yloxy)picolinate

To the solution of tert-butyl4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinate (500 mg, 1.25mmol) in 10 ml of NMP was added (1R,2R)-cyclohexane-1,2-diamine (581 mg,3.84 mmol) and DIPEA (0.995 ml, 5.76 mmol). The reaction solution wasstirred at 100° C. for 3 days. The crude reaction solution was purifiedon prep HPLC and evaporated in vacuo to give tert-butyl4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinate(240 mg, 0.544 mmol) as white powder. ES/MS m/z 442.5 (MH⁺).

Step 4. Preparation of4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinicacid

To the solution of tert-butyl4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinate(250 mg, 0566 mmol) in 10 ml of acetonitrile was added 6 M ofhydrochloric acid (1 ml, 6 mmol). The reaction solution was stirred atroom temperature for 1 hour and then at 60° C. for 2 hours. The crudereaction solution was concentrated and re-dissolved with 10 ml ofacetonitrile. The resulting solution was evaporated in vacuo to givelight brown oily product4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinicacid (215 mg, 0.56 mmol). ES/MS m/z 386.5 (MH⁺).

Step 5. Preparation ofN-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide

To the reaction solution of4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinicacid (5 mg, 39 μmol), HATU (15 mg, 39 μmol) and DIPEA (14 μL, 78 μmol)in 1 ml of NMP was added cyclopropylamine (7 ul mg, 30 μmol). Thereaction solution was stirred at room temperature for 12 hours. Thecrude reaction solution was purified on prep HPLC and evaporated invacuo to giveN-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide(1 mg, 2.3 μmol) as white powder. ES/MS m/z 425.2 (MH⁺).

Example 172 Preparation of4-(2-(cyclohexylmethoxy)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of4-(2-(cyclohexylmethoxy)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15mg, 43 μmol) was mixed with 500 μL of cyclohexylmethanol and cesiumcarbonate (42 mg, 0.13 mmol). The resulting reaction mixture was stirredat 90° C. for 12 hours. The crude reaction mixture was filtered andpurified on prep HPLC and then evaporated in vacuo to give4-(2-(cyclohexylmethoxy)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (7mg, 17.6 μmol) as powder. ES/MS m/z 398.1 (MH⁺).

Example 173 Preparation of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of(1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

To the solution of 2-chloro-6-methoxybenzo[d]thiazole (1.0 g, 5 mmol) in5.5 ml of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (910mg, 6 mmol) and DIPEA (2.44 ml, 14 mmol). The reaction solution wasstirred at 115° C. for 96 hours. The crude reaction solution waspurified by prep HPLC to give purified fractions that was combined andneutralized with solid NaHCO₃. The resulting solution was extracted withethyl acetate (2×300 ml). The combined organic layers were washed withwater (60 ml) and brine (60 ml), then dried over Na₂SO₄ and evaporatedin vacuo to give(1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1.06 g, 3.81mmol) as an ivory solid. ES/MS m/z 279.1 (MH⁺).

Step 2. Preparation of2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol

To the solution of(1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1.06 g, 3.81mmol) in 16 ml of DCM was added 1 M boron tribromide in DCM (8 ml, 8mmol) slowly at 0° C. The reaction solution was stirred at roomtemperature for 2 hours. Removal of all solvent in vacuo, followed byquenching with water (ca. 30 ml) and diluted NaHCO₃ solution, andextraction of aqueous phase with ethyl acetate (3×100 ml) and drying ofcombined organic extracts over Na₂SO₄ and subsequent removal of ethylacetate in vacuo yielded the desired product (1.16 g) as pink solid. Theresidue was purified by flash column chromatography to give2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (1.0 g, 3.78mmol) as brown solid. ES/MS m/z 265.1 (MH⁺).

Step 3. Preparation of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the mixture of2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (265 mg, 1mmol) and cesium carbonate (651 mg, 2 mmol) in 3 ml of NMP was added2-chloro-4-fluoropyridine (263 mg, 2 mmol). The reaction mixture wasstirred at 60° C. for 20 hours. The crude reaction mixture was filteredand then purified on prep HPLC to give(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas powder (341 mg, 0.9 mmol). ES/MS m/z 376.0 (MH⁺).

Example 174 Preparation of(1R,2R)-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Step 4. Preparation of(1R,2R)-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(20 mg, 40 μmol) in 400 μL of DME,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21mg, 100 μmol), Pd(dppf)₂Cl₂ (4 mg, 5 μmol) and 2M Na₂CO₃ (100 μL, 200μmol) were added. The reaction mixture was stirred at 90° C. for 24hours. The reaction mixture was poured into 10 ml of saturated NaHCO₃solution and extracted with ethyl acetate (2×30 ml). The combinedorganic layers were washed with water (2×10 ml) and brine (20 ml), thendried over Na₂SO₄ and evaporated in vacuo to give a brown solid (65 mg)that was purified on prep HPLC to give(1R,2R)-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas powder (6.4 mg). ES/MS m/z 422.2 (MH⁺).

Example 175 Preparation of(1R,2R)-2-(6-(2-(1-methyl-1H-imidazol-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(2-(1-methyl-1H-imidazol-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(11 mg, 0.029 mmol) in 0.5 ml of DMF was added Pd(dppf)₂Cl₂ (7.2 mg,0.0088 mmol), LiCl (19 mg, 0.44 mmol) and then1-methyl-5-(tributylstannyl)-1H-imidazole (44 mg, 0.117 mmol). Thereaction solution was stirred at 105-110° C. for 18 hours or done by LC.The crude reaction mixture was filtered, purified on prep HPLC andlyophilized to give(1R,2R)-2-(6-(2-(1-methyl-1H-imidazol-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (3.5 mg). ES/MS m/z 422.1 (MH⁺).

Example 176 Preparation of(1R,2R)-2-(6-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210 mg,1.08 mmol) in 2.0 ml of NMP was added Cesium Carbonate (672 mg, 2.06mmol). The reaction mixture was stirred for 5 minutes and then1,1-difluoro-2-iodoethane (197 mg, 1.03 mmol) was added and stirred atRT for 40 hours. From the above crude reaction mixture remove (0.8 ml,0.432 mol) and use. (The remaining 1.2 ml was stored in freezer). To the0.8 ml reaction mixture add(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(20 mg, 0.053 mmol), Pd(dppf)₂Cl₂ (15.2 mg, 0.019 mmol) and 2M Na₂CO₃(0.150 ml, 0.3 mmol). The reaction mixture was microwaved at 140° C. for720 seconds. The crude reaction mixture was filtered, purified on prepHPLC and lyophilized to give(1R,2R)-2-(6-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (4.6 mg). ES MS m/z 472.0 (MH⁺).

Example 177 Preparation of(1R,2R)-2-(6-(2-(4-methyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde

To the reaction mixture of2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (90 mg, 0.34mmol) in 1.9 ml of NMP was added Cesium Carbonate (232 mg, 0.71 mmol)and 4-chloropicolinaldehyde (125 mg, 0.883 mmol). The reaction mixturewas stirred at RT. for 10 minutes and then microwaved at 150° C. for 750seconds. The crude reaction mixture was filtered, purified on prep HPLCand lyophilized to give4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinaldehydeas TFA salt (88 mg). ES/MS m/z 388.1 (MH⁺) as the hydrate (+18).

Step 2. Preparation of(1R,2R)-2-(6-(2-(4-methyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde(16 mg, 0.041 mmol) in 0.75 ml of MeOH was added ammonium acetate (32mg, 0.41 mmol) and 2-oxopropanal 40% wt solution of in water (0.037 ml,0.21 mmol). The reaction mixture was stirred at 70° C. for 2 hours. Thecrude reaction mixture was concentrated, re-dissolved in 0.8 ml DMF,filtered, purified on prep HPLC and lyophilized to give(1R,2R)-2-(6-(2-(4-methyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (3.2 mg). ES/MS m/z 422.1 (MH⁺).

Example 178 Preparation of(1R,2R)-2-(6-(3-bromopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(3-bromopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (12.5 mg, 0.047mmol) in 0.4 ml of NMP was added Cesium Carbonate (39 mg, 0.118 mmol)and stirred at RT for 1-3 minutes. To this mixture was added3-bromo-4-chloropyridine (18.2 mg, 0.094 mmol). The reaction mixture wasstirred at 90° C. for 4 hours or until done by LC. The crude reactionmixture was filtered, purified on prep HPLC and lyophilized to(1R,2R)-2-(6-(3-bromopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (9.2 mg). ES/MS m/z 420.1/422.0 (MH⁺).

Example 179 Preparation of(1R,2R)-2-(6-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(3-bromopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(15 mg, 0.036 mmol) in 0.5 ml of NMP was added Pd(dppf)₂Cl₂ (8.8 mg,0.0107 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30mg, 0.143 mmol) and 2M Na₂CO₃ (0.12 ml, 0.24 mmol). The reactionsolution was stirred at 105-110° C. for 2 hours or until done by LC. Thecrude reaction mixture was filtered, purified on prep HPLC andlyophilized to give(1R,2R)-2-(6-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (5.5 mg). ES/MS m/z 422.1 (MH⁺).

Example 180 Preparation of4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinonitrile

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation ofN-(cyclohexylmethyl)-6-methoxybenzo[d]thiazol-2-amine

To the solution of 2-chloro-6-methoxybenzo[d]thiazole (900 mg, 4.5 mmol)in 4.5 ml of NMP was added cyclohexylmethanamine (865 mg, 7.65 mmol) andDIPEA (1.57 ml, 9.0 mmol). The reaction solution was stirred at 105-110°C. for 66 hours. The reaction was worked up by adding 250 ml ethylacetate and washed with 2×60 ml of saturated NaHCO₃, 3×60 ml water, 1×60ml saturated NaCl, dried with sodium sulfate, filtered and concentratedin vacuo to give N-(cyclohexylmethyl)-6-methoxybenzo[d]thiazol-2-amineas solid (1.18 grams). ES/MS m/z 277.1 (MH⁺).

Step 2. Preparation of 2-(cyclohexylmethylamino)benzo[d]thiazol-6-ol

To the solution of N-(cyclohexylmethyl)-6-methoxybenzo[d]thiazol-2-amine(1.40 g, 5.05 mmol) in 12 ml of DCM was added 1 M boron tribromide inDCM (10.6 ml, 10.6 mmol) slowly over about 3 minutes at 0° C. Thereaction solution was stirred at 0° C. for 20 min and then at RT. for 2hr. The reaction mixture was concentrated to a solid. To the residualsolids add 200 ml of ethyl acetate and 50 ml of water and stir at RT.for 10 minutes. With stirring, carefully add excess solid NaHCO₃ untilbasic. Stir at RT. about 1 hour to dissolve the solids. Remove theaqueous layer and extract with 100 ml of ethyl acetate. Combine organiclayers and wash with 1×30 ml water, 1×25 ml saturated NaCl solution anddry with sodium sulfate. This mixture was filter through a silica gelplug (1.25 in.×3 in.) and flushed with ethyl acetate. The filtrate wasconcentrated under reduced pressure to give2-(cyclohexylmethylamino)benzo[d]thiazol-6-ol as solid (1.32 grams).ES/MS m/z 263.1 (MH⁺).

Step 3. Preparation of4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinonitrile

To the reaction mixture of 2-(cyclohexylmethylamino)benzo[d]thiazol-6-ol(18 mg, 0.068 mmol) in 0.4 ml of NMP was added Cesium Carbonate (56 mg,0.171 mmol) and stirred at RT for 1-3 minutes. To this mixture was added4-chloropicolinonitrile (19 mg, 0.136 mmol). The reaction mixture wasstirred at 60° C. for 5 hours or until done by LC. The crude reactionmixture was filtered, purified on prep HPLC and lyophilized to give4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinonitrile asTFA salt (9.8 mg). ES/MS m/z 365.1 (MH⁺)

Example 181 Preparation of6-(2-(1H-tetrazol-5-yl)pyridin-4-yloxy)-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below:

Preparation of6-(2-(1H-tetrazol-5-yl)pyridin-4-yloxy)-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine

To the reaction mixture of4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinonitrile (20mg, 0.055 mmol) in 0.6 ml of NMP was added ZnCl₂ (37 mg, 0.274 mmol) andsodium azide (35.5 mg, 0.55 mmol). The reaction solution was microwavedat 170° C. for 800 seconds. The crude reaction mixture was filtered,purified on prep HPLC and lyophilized to give6-(2-(1H-tetrazol-5-yl)pyridin-4-yloxy)-N-(cyclohexylmethyl)benzo[d]thiazol-2-amineas TFA salt (6.6 mg). ES/MS m/z 408.2 (MH⁺).

Example 182 Preparation of6-(quinolin-4-yloxy)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole

To the reaction mixture of 2-(methylthio)benzo[d]thiazol-6-ol (750 mg,3.79 mmol) in 10 ml of NMP was added Cesium Carbonate (3.2 g, 9.5 mmol)and stirred at RT for 3 minutes. To this mixture was added4-chloroquinoline (682 mg, 4.17 mmol). The reaction mixture was stirredat 110° C. for 24 hours. The reaction was worked up by adding 250 mlethyl acetate and washed with 75 ml of saturated NaHCO₃, 2×60 ml water,1×50 ml saturated NaCl, dried with sodium sulfate, filtered andconcentrated in vacuo. The resulting solid residue was purified bysilica gel column chromatography, eluted with (40% EtOAc: 60% Hexanes)and concentrated in vacuo to give2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (980 mg).ES/MS m/z 325.1 (MH⁺).

Step 2. Preparation of2-(methylsulfinyl)-6-(quinolin-4-yloxy)benzo[d]thiazole

The reaction mixture of2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole (460 mg, 1.415 mmol)was dissolved in 8 ml of DCM and cooled to −5° C. A solution was made of77% MCPBA (333 mg, 1.486 mmol) and 6 ml of DCM. This solution was addedto above cooled reaction mixture dropwise over 3-4 minutes. The reactionwas stirred at −5° C. for 10 minutes, stirred at RT. for 90 minutes. Thereaction followed by LC indicated 95% completed and stalled. A newsolution was made of 77% MCPBA (25 mg, 0.1132 mmol) and 1 ml of DCM.This solution was added to above RT. reaction mixture dropwise. Thereaction was stirred for 90 minutes more with LC indicating the reactionwas complete. The reaction was worked up by adding 80 ml of DCM and 25ml of a 10% sodium thiosulfate solution and stirred at RT. for 10minutes. Aqueous layer was extracted and the DCM layer was washed with25 ml of saturated NaHCO₃, 2×25 ml 5% NaHCO₃ solution, 1×25 ml water,1×25 ml saturated NaCl, dried with sodium sulfate. About 1 gram ofSilica gel was added and stirred for 10 minutes. The mixture wasfiltered and concentrated in vacuo to give2-(methylsulfinyl)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (357mg). ES/MS m/z 341.0 (MH⁺).

Step 3. Preparation of6-(quinolin-4-yloxy)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzo[d]thiazol-2-amine

To the reaction mixture of2-(methylsulfinyl)-6-(quinolin-4-yloxy)benzo[d]thiazole (11.5 mg, 0.034mmol) in 0.4 mL of NMP was added (DIPEA) diisopropylethylamine (15 uL,0.084 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine (17.4 mg, 0.134mmol). The reaction mixture was stirred at 100° C. for 20 hours or untildone by LC. The crude reaction mixture was filtered, purified on prepHPLC and lyophilized to give6-(quinolin-4-yloxy)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzo[d]thiazol-2-amineas TFA salt (5.1 mg). ES/MS m/z 406.1 (MH⁺).

Example 183 Preparation of(1R,2R)-2-(6-(2-morpholinopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Preparation of(1R,2R)-2-(6-(2-morpholinopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(14 mg, 0.037 mmol) in 0.4 ml of NMP was added (DIPEA)diisopropylethylamine (13 ul, 0.074 mmol) and morpholine (49 mg, 0.558mmol). The reaction mixture was stirred at 110° C. for 48 hours or untildone by LC. The crude reaction mixture was filtered, purified on prepHPLC and lyophilized to give(1R,2R)-2-(6-(2-morpholinopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (3.7 mg). ES/MS m/z 427.1 (MH⁺).

Example 184(S)-6-(2-chloropyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of(S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine

To the solution of 2-chloro-6-methoxybenzo[d]thiazole (2.0 g, 10 mmol)in 10 ml of NMP was added (S)-1-cyclohexylethanamine (2.3 g, 18 mmol)and DIPEA (3.5 ml, 20 mmol). The reaction solution was stirred at 110°C. for 96 hr. The reaction was worked up by adding 170 ml ethyl acetateand washed with 1×60 ml of saturated NaHCO₃, 1×60 ml 5% NaHCO₃ solution,1×60 ml water, 1×60 ml saturated NaCl, dried with sodium sulfate,filtered and concentrated in vacuo to give(S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine as crudesolid (3.39 grams). ES/MS m/z 291.1 (MH⁺).

Step 2. Preparation of(S)-2-(1-cyclohexylethylamino)benzo[d]thiazol-6-ol

To the solution of(S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine (3.39 g, 10mmol) in 30 ml of DCM was added 1 M boron tribromide in DCM (20 ml, 20mmol) slowly at 0° C. The reaction solution was stirred at 0° C. then atRT for 2 hr. The reaction mixture was concentrated to a solid. To theresidual solids add 400 ml of ethyl acetate and 90 ml of water and stirat RT. for 10 minutes. With stirring, carefully add excess solid NaHCO₃until basic. Stir at RT about 1 hour to dissolve the solids. Remove theaqueous layer and extract with 100 ml of ethyl acetate. Combine organiclayers and wash with 1×50 ml water, 1×50 ml saturated NaCl solution, drywith sodium sulfate, filter and concentrate under reduced pressure. Theresulting solid was purified by silica gel column chromatography, elutedwith (30% EtOAc: 70% Hexanes) and concentrated in vacuo to give(S)-2-(1-cyclohexylethylamino)benzo[d]thiazol-6-ol as solid (2.0 grams).ES/MS m/z 277.1 (MH⁺).

Step 3. Preparation of(S)-6-(2-chloropyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amine

To the mixture (S)-2-(1-cyclohexylethylamino)benzo[d]thiazol-6-ol (270mg, 0.974 mmol) and cesium carbonate (794 mg, 2.44 mmol) in 3.6 ml ofNMP was added 2-chloro-4-fluoropyridine (254 mg, 1.95 mmol). Thereaction mixture was stirred at 60° C. for 18 hours or until done by LC.The crude reaction mixture was filtered, purified on prep HPLC andlyophilized to give(S)-6-(2-chloropyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amineas TFA salt (298 mg). ES/MS m/z 388.1 (MH⁺).

Example 185 Preparation of(S)-6-(2,3′-bipyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amine

Preparation of(S)-6-(2,3′-bipyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amine

To the reaction mixture of(S)-6-(2-chloropyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amine(15 mg, 0.039 mmol) in 0.6 ml of DME,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (32 mg, 0.155mmol), Pd(dppf)₂Cl₂ (7.9 mg, 0.0096 mmol) and 2M Na₂CO₃ (0.18 ml, 0.36mmol) were added. The reaction solution was stirred at 100-105° C. for90 minutes or until done by LC. The crude reaction mixture wasconcentrated to solid, re-dissolved in 0.8 ml DMF, filtered, purified onprep HPLC and lyophilized to give(S)-6-(2,3′-bipyridin-4-yloxy)-N-(1-cyclohexylethyl)benzo[d]thiazol-2-amineas TFA salt (5.2 mg). ES/MS m/z 431.2 (MH⁺)

Example 186(S)—N-(1-cyclohexylethyl)-6-(2-(4-methyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of(S)-4-(2-(1-cyclohexylethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde

To the reaction mixture of(S)-2-(1-cyclohexylethylamino)benzo[d]thiazol-6-ol (110 mg, 0.40 mmol)in 2.0 ml of NMP was added Cesium Carbonate (272 mg, 0.834 mmol) and4-chloropicolinaldehyde (146 mg, 1.03 mmol). The reaction mixture wasstirred at RT. for 20 minutes and then microwaved at 150° C. for 750seconds. The crude reaction mixture was filtered, purified on prep HPLCand lyophilized to give(S)-4-(2-(1-cyclohexylethylamino)benzo[d]thiazol-6-yloxy)picolinaldehydeas TFA salt (105 mg). ES/MS m/z 400.2 (MH⁺) as the hydrate (+18).

Step 2. Preparation of(S)—N-(1-cyclohexylethyl)-6-(2-(4-methyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

To the reaction mixture of(S)-4-(2-(1-cyclohexylethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde(15 mg, 0.038 mmol) in 0.6 ml of methanol was added ammonium acetate (29mg, 0.38 mmol) and 2-oxopropanal 40% wt solution of in water (0.034 ml,0.19 mmol). The reaction mixture was stirred at 70° C. for 2 hours. Thecrude reaction mixture was concentrated to solid, re-dissolved in 0.8 mlDMF, filtered, purified on prep HPLC and lyophilized to give(S)—N-(1-cyclohexylethyl)-6-(2-(4-methyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amineas TFA salt (6.5 mg). ES/MS m/z 434.2 (MH⁺).

Example 187 Preparation of(1R,2R)-2-(6-(2-(1H-imidazol-1-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Preparation of(1R,2R)-2-(6-(2-(1H-imidazol-1-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(12 mg, 0.032 mmol) in 0.55 ml of NMP was added (DIPEA)diisopropylethylamine (17 ul, 0.096 mmol) and 1H-imidazole (180 mg, 2.64mmol). The reaction mixture was followed by LC, LCMS and microwaved asfollows: (150° C. for 750 seconds, 230° C. for 750 seconds, 250° C. for1000 seconds, again at 250° C. for 1000 seconds). The crude reactionmixture was filtered, purified on prep HPLC and lyophilized to give(1R,2R)-2-(6-(2-(1H-imidazol-1-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (1.4 mg). ES/MS m/z 408.2 (MH⁺).

Example 188 Preparation of(1R,2R)-2-(6-(2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Step 1. Preparation of tert-butyl4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(11 mg, 0.029 mmol) in 0.5 ml of DME, tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(36 mg, 0.117 mmol), Pd(dppf)₂Cl₂ (7.2 mg, 0.0088 mmol) and 2M Na₂CO₃(0.125 ml, 0.25 mmol) were added. The reaction solution was stirred at105-110° C. for 24 hours or until done by LC. The crude reaction mixturewas concentrated to solid re-dissolved in 0.8 ml DMF, filtered, purifiedon prep HPLC and lyophilized to give tert-butyl4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateas TFA salt (2.5 mg). ES/MS m/z 523.1 (MH⁺).

Step 2. Preparation of(1R,2R)-2-(6-(2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the solid of tert-butyl4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.5 mg, 0.0039 mmol) was added 4M HCL in Dioxane (1 ml, 4.0 mmol). Thereaction mixture was stirred at RT for 45 minutes. The crude reactionmixture was concentrated to solid and lyophilized to give(1R,2R)-2-(6-(2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas HCl salt (1.4 mg). ES/MS m/z 423.1 (MH⁺).

Example 189 Preparation of4-(2-((1s,4s)-4-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below

Step 1. Preparation of tert-butyl(1s,4s)-4-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexylcarbamate

To the reaction mixture ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15mg, 0.043 mmol) in 0.4 ml of NMP was added tert-butyl(1s,4s)-4-aminocyclohexylcarbamate (47 mg, 0.215 mmol) and (DIPEA)diisopropylethylamine (22 ul, 0.129 mmol). The reaction mixture wasstirred at 105-100° C. for 20 hr or until done by LC. The crude reactionsolution was purified by prep HPLC and lyophilized to give tert-butyl(1s,4s)-4-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexylcarbamate(16 mg) as TFA salt. ES/MS m/z 498.2 (MH⁺).

Step 2. Preparation of4-(2-((1s,4s)-4-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solid of tert-butyl(1s,4s)-4-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexylcarbamate(16 mg, 0.032 mmol) was added 2M HCL in Ethyl Ether (2 ml, 4.0 mmol).The reaction mixture was stirred at RT for 60 minutes. The crudereaction mixture was concentrated to solid and lyophilized to give4-(2-((1s,4s)-4-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamideas HCl salt (12.0 mg). ES/MS m/z 398.1 (MH⁺).

Example 190 Preparation of4-(2-((1s,4s)-4-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below

Preparation4-(2-((1s,4s)-4-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the reaction mixture of4-(2-((1s,4s)-4-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(9.0 mg, 0.0226 mmol) in 0.6 ml of NMP was added (TEA) triethylamine (19ul, 0.136 mmol) and then acetic anhydride (7.0 mg, 0.0678 mmol). Thereaction mixture was stirred at RT. for 90 minutes. The crude reactionsolution was purified by prep HPLC and lyophilized to give4-(2-((1s,4s)-4-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(8.7 mg) as TFA salt. ES/MS m/z 440.2 (MH⁺).

Example 191 Preparation of4-(2-((1s,4s)-4-isobutyramidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

The subject compound was prepared according to the general Scheme below:

Preparation4-(2-((1s,4s)-4-isobutyramidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the reaction mixture of isobutyric acid (4.4 mg, 0.050 mmol) in 0.3ml of NMP was added HATU (17.1 mg, 0.045 mmol) and then (DIPEA)diisopropylethylamine (11 ul, 0.0625 mmol). The reaction mixture wasstirred at RT. for 10-15 minutes. To the above reaction mixture wasadded a solution of4-(2-((1s,4s)-4-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(10 mg, 0.025 mmol) and (DIPEA) diisopropylethylamine (13 ul, 0.075mmol) in 0.3 ml of NMP. The reaction solution was stirred at RT. for 18hours. The crude reaction solution was purified by prep HPLC andlyophilized to give4-(2-((1s,4s)-4-isobutyramidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(4.0 mg) as TFA salt. ES/MS m/z 468.3 (MH⁺).

Example 192 Preparation of(1R,2R)-2-(6-(6-fluoroquinolin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(6-fluoroquinolin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (15.1 mg, 0.057mmol) in 0.4 ml of NMP was added Cesium Carbonate (47 mg, 0.143 mmol)and stirred at RT for 1-3 minutes. To this mixture was added4-chloro-6-fluoroquinoline (21 mg, 0.114 mmol). The reaction mixture wasstirred at 105-110° C. for 18 hours or until done by LC. The crudereaction mixture was filtered, purified on prep HPLC and lyophilized togive(1R,2R)-2-(6-(6-fluoroquinolin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (9.2 mg). ES/MS m/z 410.1 (MH⁺).

Example 1934-(2-(cyclohexylmethylamino)-4-methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Step 1. Synthesis of 4-(4-amino-3-methylphenoxy)-N-methylpicolinamide

To the solution of 4-amino-m-cresol (125 mg, 1.01 mmol, 1.0 eq) in 1 mLof NMP was added 4-chloro-N-methylpicolinamide (189 mg, 1.11 mmol, 1.1eq) and cesium carbonate (658 mg, 2.02 mmol, 2.0 eq) at roomtemperature. The reaction mixture was stirred at 75° C. for 12 hours,thereafter the mixture was diluted with water (ca. 50 mL) and aqueouslayer extracted with ethyl acetate (ca. 50 mL×3). Combined organiclayers were dried over sodium sulfate, filtered and condensed underreduced pressure to give sufficiently pure crude product which wascarried to next step without further purification. LC/MS (m/z) [258.1](MH⁺).

Step 2. Synthesis of4-(2-amino-4-methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of 4-(4-amino-3-methylphenoxy)-N-methylpicolinamide (25mg, 0.097 mmol, 1.0 eq) in 1 mL of cold acetic acid was added ammoniumthiocyanate (11 mg, 0.145 mmol, 1.5 eq). After stirring for a fewminutes, bromine (6 μL, 0.116 mmol, 1.2 eq) was injected dropwise andreaction stirred at room temperature for 3 hours. Thereafter, reactionwas quenched with NaHCO₃ saturated solution (ca. 10 mL) and extractedwith ethyl acetate (ca. 25 mL×3), combined organic extracts were driedover sodium sulfate and condensed under reduced pressure to givesufficiently pure crude product which was carried to next step withoutfurther purification. LC/MS (m/z) [315.1] (MH⁺).

Step 3. Synthesis of4-(2-(cyclohexylmethylamino)-4-methylbenzo[d]thiazol-6-yloxy)methylpicolinamide

To the solution of4-(2-amino-4-methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide (30 mg,0.095 mmol, 1.0 eq) in 1 mL of NMP was added bromomethyl cyclohexane (20μL, 0.142 mmol, 1.5 eq) and potassium carbonate (40 mg, 0.285 mmol, 3.0eq) at room temperature. The reaction mixture was stirred at 80° C. for12 hours and thereafter purified via reverse phase HPLC. LC/MS (m/z)[411.1] (MH⁺)

Example 1944-(4-chloro-2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Step 1. Synthesis of 4-(4-amino-3-chlorophenoxy)-N-methylpicolinamide

Prepared following the procedure outlined in Step 1 of Example 1 LC/MS(m/z) [278.1] (MH⁺)

Step 2. Synthesis of4-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Prepared following the procedure outlined in Step 2 of Example 1. LC/MS(m/z) [335.0] (MH⁺)

Step 3. Synthesis of4-(4-chloro-2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of4-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide (30 mg,0.089 mmol, 1.0 eq) in 2 mL of NMP was added bromomethyl cyclohexane (18μL, 0.134 mmol, 1.5 eq) and potassium carbonate (36 mg, 0.267 mmol, 3.0eq) at room temperature. The reaction mixture was stirred at 80° C. for2 hours and thereafter purified via reverse phase HPLC. LC/MS (m/z)[431.0] (MH+)

Example 1954-(7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Step 1. Synthesis of 7-bromo-2-chloro-6-methoxybenzo[d]thiazole

To the solution of 2-chloro-6-methoxy-benzothiazole (200 mg, 1.0 mmol,1.0 eq) in 5 mL of NMP was added N-bromosuccinimide (213 mg, 1.20 mmol,1.2 eq) at room temperature. The reaction mixture was stirred at 75° C.for >24 hours with subsequent addition of NBS in small batches forreaction progress, thereafter the mixture was diluted with water (ca.100 mL) and aqueous layer extracted with ethyl acetate (ca. 150 mL×3).Combined organic layers were dried over sodium sulfate, filtered andcondensed under reduced pressure. Purification on ISCO using gradient0%-50% ethyl acetate-hexane gave 336 mg of product as off white fluffypowder in 60% yields structure of which was confirmed by H⁺NMR. LC/MS(m/z) [279.9] (MH⁺)

Step 2. Synthesis of(1R,2R)-2-(7-bromo-6-methoxybenzo[d]thiazol-2ylamino)cyclohexanol

To the solution of 7-bromo-2-chloro-6-methoxybenzo[d]thiazole (150 mg,0.539 mmol, 1.0 eq) in 1 mL of NMP was added (1R,2R)-2-aminocyclohexanolhydrochloride (0.123 mg, 0.809 mmol, 1.5 eq) and DIPEA (263 μL, 1.503mmol, 2.8 eq) at room temperature. The reaction mixture was stirred at125° C. for 12 hours, thereafter the mixture was diluted with saturatedsodium bicarbonate solution (ca. 100 mL) and aqueous layer extractedwith ethyl acetate (ca. 200 mL×3). Combined organic layers were driedover sodium sulfate, filtered and condensed under reduced pressure togive crude product as brown oil which was sufficiently pure and wascarried to next step without further purification. LC/MS (m/z) [359.0](MH⁺)

Step 3. Synthesis of7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)-benzo[d]thiazol-6-ol

To the solution of(1R,2R)-2-(7-bromo-6-methoxybenzo[d]thiazol-2-ylamino) cyclohexanol (191mg, 0.537 mmol, 1.0 eq) in 10 mL of DCM was added 1 M solution of borontribromide (ca. 3.0 mL, 2.68 mmol, 5.0 eq) at room temperature. Thereaction mixture was refluxed for 12 hours, thereafter the mixture wasdiluted with saturated sodium bicarbonate (ca. 100 mL) till PH=7 andaqueous layer extracted with ethyl acetate (ca. 150 mL×3). Combinedorganic layers were dried over sodium sulfate, filtered and condensedunder reduced pressure to give sufficiently pure crude product which wascarried to next step without further purification LC/MS (m/z) [345.0](MH⁺).

Step 4. Synthesis of4-(7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (50 mg,0.145 mmol, 1.0 eq) in 1 mL of NMP was added4-chloro-N-methylpicolinamide (29 mg, 0.174 mmol, 1.2 eq) and cesiumcarbonate (165 mg, 0.507 mmol, 3.5 eq) at room temperature. The reactionmixture was stirred at 80° C. for ca. 12 hours, thereafter the mixturewas purified on the reverse phase HPLC. LC/MS (m/z) [479.0] (MH⁺)

Example 1964-(2-((1R,2R)-2-hydroxycyclohexylamino)-7-methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Step 1. Synthesis of2-((1R,2R)-2-hydroxycyclohexylamino)-7-methylbenzo[d]thiazol-6-ol

To the solution of7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (117mg, 0.34 mmol, 1.0 eq) in 1 mL DMF in a microwave vial was addedtrimethylboraxine (128 mg, 1.02 mmol, 3.0 eq), Pd(Cl₂)dPPf (27 mg, 0.034mmol, 0.1 eq) and 1 mL of 2M Na₂CO₃ solution at room temperature.Thereafter, the reaction mixture was heated in the microwave at 120° C.for 15 minutes. The reaction was quenched with saturated NaHCO₃ solution(25 ml) and the aqueous phase extracted with ethyl acetate (50 mL×3),combined organic layers dried over Na₂SO₄, filtered and condensed underreduced pressure. Purification over ISCO using a gradient of 0%-18%methanol-DCM gave 17 mg of product as brownish powder in 17% yield.LC/MS (m/z) [279.1] (MH⁺)

Step 2. Synthesis of4-(2-((1R,2R)-2-hydroxycyclohexylamino)-7-methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Prepared following the procedure in example 543 step 4. LC/MS (m/z)[413.1] (MH⁺)

Example 1974-(7-chloro-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Step 1. Synthesis of 7-chloro-2-(methylthio)benzo[d]thiazol-6-ol

To the solution of 2-(methylthio)benzo[d]thiazol-6-ol (500 mg, 2.53mmol, 1.0 eq) in 10 mL of NMP was added N-chlorosuccinimide (507 mg,3.80 mmol, 1.5 eq) at room temperature. The reaction mixture was stirredat room temperature for 1 hour thereafter the mixture was diluted withsaturated sodium bicarbonate solution (ca. 100 mL) and aqueous layerextracted with DCM (ca. 150 mL×3). Combined organic layers were driedover sodium sulfate, filtered and condensed under reduced pressure.Purification on ISCO using gradient 0%-100% ethyl acetate-hexane gave283.39 mg of product in 48% yields structure of which was confirmed byH⁺NMR. LC/MS (m/z) [232.0] (MH⁺)

Step 2. Synthesis of4-(7-chloro-2-(methylthio)benzo[d]thiazol-6-yloxy)-N methyl picolinamide

To the solution of 7-chloro-2-(methylthio)benzo[d]thiazol-6-ol (80 mg,0.346 mmol, 1.0 eq) in 1 mL of NMP was added4-chloro-N-methylpicolinamide (88 mg, 0.519 mmol, 1.5 eq) and cesiumcarbonate (281 mg, 0.865 mmol, 2.5 eq) at room temperature. The reactionmixture was stirred at 85° C. for >48 hours till ca. 75%-80% completion,thereafter the mixture was diluted with water (ca. 50 mL) and aqueouslayer extracted with ethyl acetate (ca. 50 mL×3). Combined organiclayers were dried over sodium sulfate, filtered and condensed underreduced pressure to give crude product which was purified on ISCO usinggradient 0%-100% ethyl acetate-hexane mixture to give 64 mg of productin 50% yield. LC/MS (m/z) [366.0] (MH⁺)

Step 3. Synthesis of4-(7-chloro-2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of4-(7-chloro-2-(methylthio)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(64 mg, 0.175 mmol, 1.0 eq) in 5 mL of DCM was added MCPBA (33 mg, 0.192mmol, 1.1 eq) at 0° C. and reaction stirred for 30-45 min. Thereafter,it was quenched with water (10 mL) and aqueous phase extracted withethyl acetate (25 mL×5), combined organic layers dried over sodiumsulfate, filtered and condensed under reduced pressure to yield crudeproduct which was sufficiently pure and was carried to next step withoutfurther purification. LC/MS (m/z) [382.0] (MH⁺)

Step 4. Synthesis of4-(7-chloro-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of4-(7-chloro-2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)-Nmethylpicolinamide(10 mg, 0.026 mmol, 1.0 eq) in NMP was added (1R,2R)-2-aminocyclohexanolhydrochloride (6 mg, 0.039 mmol, 1.5 eq) and DIPEA (13 μL, 0.078 mmol,3.0 eq) and reaction mixture heated at 160° C. in microwave for 15 min.Thereafter, the product was purified via reverse phase HPLC. LC/MS (m/z)[433.1] (MH⁺)

Example 1984-(2-(cyclohexylmethylamino)-5-fluorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

Step 1. Synthesis of 5-fluoro-6-methoxybenzo[d]thiazol-2-amine

Reference used—“Synthesis and biological activity ofα-[(6-chloro-5-fluoro-2 benzothiazolyl)amino]acetanilides”. Pattan, S.R.; Narendra, Babu S. N.; Angadi, J. S. Dept. of Mechanical Chemistry,K.L.E.S's College of Pharmacy, Belg. Indian Drugs (2002), 39(10),515-517.

To the solution of 3-fluoro-p-anisidine (1.00 g, 7.09 mmol, 1.0 eq) in30 mL of cold acetic acid was added ammonium thiocyanate (1.07 g, 14.18mmol, 2.0 eq). After stirring for a few minutes, bromine (437 μL, 8.50mmol, 1.2 eq) in 6 mL acetic acid was injected slowly dropwise throughaddition funnel and reaction stirred at room temperature for 3 hours.Thereafter, acetic acid was removed under reduced pressure and NaHCO₃saturated solution (100 mL) added to the residue which was extractedwith ethyl acetate (125 mL×3), combined organic extracts were dried oversodium sulfate and condensed under reduced pressure to give crude whichwas sufficiently pure and was carried to next step without furtherpurification.

NMR (H⁺) (DMSO) 1H (d) 7.51, 7.48, 2H (s) 7.34, 1H (d) 7.17, 7.13, 3H(s) 3.78. LC/MS (m/z) [199.0] (MH⁺)

Step 2. Synthesis ofN-(cyclohexylmethyl)-5-fluoro-6-methoxybenzo[d]thiazol-2-amine

To the solution of 5-fluoro-6-methoxybenzo[d]thiazol-2-amine (350 mg,1.76 mmol, 1.0 eq) in 2 mL of NMP was added bromomethyl cyclohexane (370μL, 2.65 mmol, 1.5 eq) and potassium carbonate (366 mg, 2.65 mmol, 1.5eq) at room temperature. The reaction mixture was stirred at 80° C. for24 hours with subsequent addition of reagents till reaction completionand thereafter quenched with saturated sodium bicarbonate solution (100mL) which was then extracted with ethyl acetate (125 mL×3), combinedorganic layers dried over sodium sulfate, filtered and condensed underreduced pressure. Purification of the crude over ISCO using slowgradient of 0%-50% ethyl acetate-hexane gave 310 mg of product in 60%yield. LC/MS (m/z) [295.1] (MH+)

Step 3. Synthesis of2-(cyclohexylmethylamino)-5-fluorobenzo[d]thiazol-6-ol

To the solution ofN-(cyclohexylmethyl)-5-fluoro-6-methoxybenzo[d]thiazol-2-amine (114 mg,0.387 mmol, 1.0 eq) in 10 mL of DCM was added 1M solution of borontribromide (ca. 1.0 mL, 0.775 mmol, 2.0 eq) at room temperature. Thereaction mixture was stirred for 2 hours, thereafter the mixture wasdiluted with saturated sodium bicarbonate solution (ca. 100 mL) tillPH=7 and aqueous layer extracted with ethyl acetate (ca. 150 mL×3).Combined organic layers were dried over sodium sulfate, filtered andcondensed under reduced pressure to give crude product which wassufficiently pure and was carried to next step without furtherpurification. LC/MS (m/z) [281.1] (MH⁺)

Step 4. Synthesis of4-(2-(cyclohexylmethylamino)-5-fluorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide

To the solution of2-(cyclohexylmethylamino)-5-fluorobenzo[d]thiazol-6-ol (25 mg, 0.089mmol, 1.0 eq) in 2 mL of NMP was added 4-chloro-N-methylpicolinamide (18mg, 0.107 mmol, 1.2 eq) and cesium carbonate (86 mg, 0.267 mmol, 3.0 eq)at room temperature. The reaction mixture was stirred at 85° C. for 12hours, thereafter the mixture was purified on reverse phase HPLC giving1.6 mg of product as TFA salt in ca. 3.5% yield. LC/MS (m/z) [415.1](MH⁺)

Example 199N-methyl-4-(2-(4-((4-methylpiperazin-1-yl)methyl)benzylamino)benzo[d]thiazol-6-yloxy)picolinamide

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25mg, 0.072 mmol, 1.0 eq) in 2 mL of NMP was added(4-((4-methylpiperazin-1-yl)methyl)phenyl)methanamine (23 mg, 0.108mmol, 1.5 eq) and DIPEA (37 μL, 0.216 mmol, 3.0 eq) and reaction mixtureheated at 80° C. in oil bath for 12 hours. Thereafter, the product waspurified via reverse phase HPLC. LC/MS (m/z) [503.1] (MH⁺).

Example 200N-methyl-4-(2-(2-(2-(4-methylpiperazin-1-yl)ethoxy)phenylamino)benzo[d]thiazol-6-yloxy)picolinamide

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25mg, 0.072 mmol, 1.0 eq) in 1 mL of IPA and 1 mL conc. HCl was added2-(2-(4-methylpiperazin-1-yl)ethoxy) aniline (25 mg, 0.108 mmol, 1.5 eq)and reaction mixture heated at 80° C. in oil bath for 2 hours.Thereafter, the product was purified via reverse phase HPLC. Thisprocedure was generalized for other analogues for which progress of thereaction was monitored by LC-MS and amount of aniline and reaction timeadjusted as needed. LC/MS (m/z) [519.1] (MH⁺)

Example 2014-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]oxazol-6-yloxy)-N-methylpicolinamide

To the solution ofN-methyl-4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)picolinamide (25mg, 0.075 mmol, 1.0 eq) in 1 mL of NMP was added(1R,2R)-2-aminocyclohexanol hydrochloride (17 mg, 0.112 mmol, 1.5 eq)and DIPEA (40 μL, 0.225 mmol, 3.0 eq) and reaction mixture stirred atroom temperature for 48 hours. Thereafter, the product was purified viareverse phase HPLC. LC/MS (m/z) [383.1] (MH⁺)

Intermediates Synthesis of 4-chloro-N-methylpyridine-3-carboxamide

Step 1. To a suspension of 4-chloronicotinic acid (1.57 g, 10.0 mmol,1.0 eq) in 25 mL of toluene was added thionyl chloride (1.8 mL, 25.0mmol, 2.5 eq) at room temperature. The reaction mixture was stirred at100° C. for 3 hours. The mixture was concentrated under reducedpressure, dissolved in 25 mL of toluene and concentrated again to givecrude 4-chloronicotinoyl chloride hydrochloride salt, which was used inthe next step without further purification.

Step 2. To a suspension of crude 4-chloronicotinoyl chloridehydrochloride in 25 mL of THF was added methylamine solution (2M in THF,20 mL, 40 mmol, 4.0 eq) at 0° C. The reaction mixture was stirred atroom temperature for 1 hour and concentrated under reduced pressure. Thecrude material was dissolved in ethylacetate (75 mL) andwater/brine/saturated sodium bicarbonate solution (1/1/1, 75 mL). Theseparated aqueous layer was extracted with EtOAc. The combined organiclayers were washed with water/brine/saturated sodium bicarbonatesolution (1/1/1, 25 mL) and brine (25 mL) and dried over sodium sulfate.Removal of the solvent under reduced pressure afforded the titlecompound as orange solid (400 mg, 24%), which was used without furtherpurification. MH+=171.0, Rt=0.55 min.

Synthesis of 4-chloro-N′,N′-dimethylpyridine-2-carboxhydrazide

To a suspension of 4-chloropicolinoyl chloride hydrochloride (352 mg,2.0 mmol, 1.0 eq) in 10 mL of THF were added N,N-dimethylhydrazine (120mg, 2.0 mmol, 1.0 eq) and N,N-diisopropylethylamine (383 μL, 2.2 mmol,1.1 eq) at room temperature. The reaction mixture was stirred for 15 minand diluted with water (25 mL) and EtOAc (50 mL). The separated organiclayer was washed with brine (25 mL), saturated sodium bicarbonatesolution (25 mL) and dried over sodium sulfate. Concentration underreduced pressure gave the title compound as colorless solid (223 mg,56%), which was used without further purification. MH+=200, Rt=1.42 min.

Synthesis of 4-chloro-N-methylpicolinamide and 4-chloropicolinoylchloride

Prepared following the method described in “A Scaleable Synthesis of BAY43-9006: A Potent Raf Kinase Inhibitor for the treatment of cancer”.Donald Bankston, Jacques Dumas, Reina Natero, Bernd Riedl,Mary-Katherine Monahan, Robert Sibley; Bayer Research Center.Pharmaceutical Division. Organic Process Research and Development 2002(6) 777-781.

Synthesis of (1R,2R)-2-aminocyclohexanol hydrochloride

To an ice bath cooled solution of amine(1R,2R)-(−)-2-Benzyloxycyclohexylamine (20 g, 97.4 mmol) in dry MeOH(390 mL) was added 4.0 M HCl solution in dioxane (49 mL, 195 mmol)slowly via syringe. The ice bath was removed and resulting solution wassparged with N₂ for 10 min. 10% Pd/C (3 g, 28 mmol) was added to thesolution and the reaction was purged with H₂ and maintained under a H₂atmosphere. After 4 h, an additional 10 mL of 4.0 M HCl solution indioxane was added² and the reaction was maintained under a H₂ atmosphereovernight. Upon completion (followed by LCMS), the reaction was filteredthrough a thin, tightly packed pad of Celite and the collected solidswere washed successively with MeOH and EtOAc. The combined organicfiltrates were evaporated and dried under vacuum gave(1R,2R)-2-aminocyclohexanol hydrochloride as a pale-colored solid, (13.8g, 91 mmol, 93%). LCMS m/z 116.0 (MH⁺), t_(R)=0.37 min.

(1S,2S)-2-aminocyclohexanol hydrochloride was prepared in the samemanner.

Example 202 4-chloro-N-isobutoxypicolinamide

To a suspension of 4-chloropicolinoyl chloride hydrochloride (1.0 g,5.68 mmol, 1.0 eq) in 25 ml of THF were added O-isobutylhydroxylaminhydrochloride (785 mg, 6.25 mmol, 1.1 eq) and N,N-diisopropylethylamine(2.97 ml, 17.0 mmol, 3.0 eq) at room temperature. The reaction mixturewas stirred for 30 min and diluted with water (25 mL) and EtOAc (50 mL).The separated organic layer was washed with brine (25 mL), saturatedsodium bicarbonate solution (2×25 mL) and dried over sodium sulfate.Concentration under reduced pressure gave the title compound ascolorless solid (870 mg, 67%), which was used without furtherpurification. ES/MS m/z 229.0 (MH⁺), Rt=2.61 min.

Example 2034-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)-N-isobutoxypicolinamide

To the reaction mixture 2-(cyclohexylmethylamino)benzo[d]thiazol-6-ol(30 mg, 0.114 mmol)) and cesium carbonate (326 mg, 0.228 mmol) in 1.2 mlof DMF was added 4-chloro-N-isobutoxypicolinamide (40 mg, 0.171 mmol).The reaction mixture was stirred at rt for 10 min and then microwaved at130° C. for 3×20 min. The crude reaction mixture was filtered, purifiedon preparative HPLC and lyophilized to give the title compound as itsTFA salt as a white solid (15 mg, 23%). ES/MS m/z 455.1 (MH⁺), Rt=2.90min.

Example 2044-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-isobutoxypicolinamide

Prepared as in the preceeding example. ES/MS m/z 457.0 (MH⁺), Rt=2.35min.

Example 205N-(cyclohexylmethyl)-6-(2-(4,5-dimethyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of(1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

To the solution of tert-butyl4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinate (500 mg, 1.28mmol) in 8.0 ml of NMP was added cyclohexylmethanamine (407 mg, 3.6mmol) and DIPEA (0.887 ml, 5.12 mmol). The reaction solution was stirredat 110° C. for 12 hours or until done by LCMS. The crude reactionmixture was filtered, purified on prep HPLC and lyophilized to givetert-butyl4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinate as TFAsalt (420 mg). ES/MS m/z 440.2 (MH⁺).

Step 2. Preparation of(4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)methanol

To the solution of tert-butyl4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinate (420 mg,1.14 mmol) under argon in 50 ml of THF was added 1 M LAH solution in THF(3.41 ml, 3.41 mmol) slowly at room temperature. The reaction mixturewas stirred at room temperature for 30 minutes. The crude reactionmixture was worked up by carefully adding methanol (5 ml), then 6M NaOH(5 ml), and water (5 ml) with stirring at room temperature. The aluminumsalts were allowed to precipitate out. Ethyl acetate (200 ml) was addedand the organic layer was decanted off from salts. The salts were washedagain with ethyl acetate (100 ml) and decanted. The organic layers werecombined and washed with brine (2×50 ml), dried with Na₂SO₄, filteredand concentrated. The resulting solid residue was purified by silica gelcolumn chromatography, eluted with (5% methanol 95% DCM) andconcentrated in vacuo to give(4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)methanolas solid (157 mg). ES/MS m/z 370.2 (MH⁺).

Step 3. Preparation of4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde

To the solution of(4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)methanol(30 mg, 0.081 mmol) in 2 ml of THF and 2 ml of DCM was added Dess-MartinPeriodinane (38 mg, 0.089 mmol). The reaction mixture was stirred atroom temperature for 30 minutes. The crude reaction mixture diluted withethyl acetate (60 ml), washed with saturated sodium bicarbonate (2×15ml), brine (1×15 ml), dried with Na₂SO₄, filter and concentrated invacuo to give4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde assolid (29 mg). ES/MS m/z 386.1 (MH⁺) as the hydrate (+18).

Step 4. Preparation ofN-(cyclohexylmethyl)-6-(2-(4,5-dimethyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

To the solution of4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde (15mg, 0.041 mmol) in 1.0 ml of methanol was added ammonium acetate (32 mg,0.41 mmol) and biacetyl (14 mg, 0.163 mmol). The reaction mixture wasstirred at 70° C. for 2 hours or until done by LCMS. The crude reactionmixture was concentrated to solid, re-dissolved in 0.8 ml NMP, filtered,purified on prep HPLC and lyophilized to giveN-(cyclohexylmethyl)-6-(2-(4,5-dimethyl-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amineas TFA salt (3.0 mg). ES/MS m/z 434.2 (MH⁺).

Example 206N-(cyclohexylmethyl)-6-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

The subject compound was prepared according to the general Scheme below

To the solution of sodium acetate (300 mg, 3.7 mmol) in 1.6 ml of waterwas added 3,3-dibromo-1,1,1-trifluoropropan-2-one (500 mg, 1.85 mmol).The reaction mixture was stirred at 100° C. for 1 hour. From the abovecrude reaction mixture remove approximately (0.5 ml, 0.46 mol), cool toroom temperature. This crude mixture was added to a solution of4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde (15mg, 0.041 mmol) in 2 ml of methanol. To the crude reaction mixture wasadded ammonium hydroxide (28%-30%) solution (0.5 ml, 4 mmol). Thereaction mixture was stirred at room temperature for 18 hours or untildone by LCMS. The crude reaction mixture was concentrated to solid,re-dissolved in 0.8 ml NMP, filtered, purified on prep HPLC andlyophilized to giveN-(cyclohexylmethyl)-6-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amineas TFA salt (3.0 mg). ES/MS m/z 474.2 (MH⁺).

Example 207(1R,2R)-2-(6-(6′-(pyrrolidin-1-yl)-2,3′-bipyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of(1R,2R)-2-(6-(6′-fluoro-2,3′-bipyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(130 mg, 0.345 mmol) in 5.0 ml of DME,2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (268mg, 1.21 mmol), Pd(dppf)₂Cl₂ (56 mg, 0.069 mmol) and 2M Na₂CO₃ (1.05 ml,2.1 mmol) were added. The reaction solution was stirred at 105° C. for 2hours or until done by LC. The crude reaction mixture was concentratedto solid, re-dissolved in 3 ml of DMF, filtered, purified on prep HPLCand lyophilized to give(1R,2R)-2-(6-(6′-fluoro-2,3′-bipyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (149 mg). ES/MS m/z 437.1 (MH⁺).

Step 2. Preparation of(1R,2R)-2-(6-(6′-(pyrrolidin-1-yl)-2,3′-bipyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(6′-fluoro-2,3′-bipyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(11 mg, 0.0252 mmol) in 0.4 ml of NMP was added (DIPEA)diisopropylethylamine (13 ul, 0.0756 mmol) and pyrrolidine (14.4 mg,0.202 mmol). The reaction mixture was stirred at 105-110° C. for 20hours or until done by LC. The crude reaction mixture was filtered,purified on prep HPLC and lyophilized to give(1R,2R)-2-(6-(6′-(pyrrolidin-1-yl)-2,3′-bipyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (2.3 mg). ES/MS m/z 488.1 (MH⁺).

Example 208(1R,2R)-2-(6-(2-(4-(pyrrolidin-1-ylmethyl)phenyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)benzaldehyde

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(70 mg, 0.186 mmol) in 2.5 ml of NMP,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (130 mg,0.558 mmol), Pd(dppf)₂Cl₂ (38 mg, 0.0465 mmol) and 2M Na₂CO₃ (0.56 ml,1.12 mmol) were added. The reaction solution was stirred at 110° C. for4 hours or until done by LC. The crude reaction mixture was filtered,purified on prep HPLC and lyophilized to give4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)benzaldehydeas TFA salt (61 mg). ES/MS m/z 446.0 (MH⁺).

Step 2. Preparation of(1R,2R)-2-(6-(2-(4-(pyrrolidin-1-ylmethyl)phenyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)benzaldehyde(12 mg, 0.027 mmol) in 0.6 ml of NMP was added in order pyrrolidine(19.2 mg, 0.27 mmol), excess acetic acid (0.060 ml, 1.0 mmol) andtriethyl orthoformate (20 mg, 0.135 mmol). The reaction mixture wasstirred at room temperature for 20 minutes. To this reaction mixture wasadded sodium triacetoxyborohydride (14.3 mg, 0.0675 mmol). The reactionmixture was stirred at room temperature for 18 hours. The crude reactionmixture was filtered, purified on prep HPLC and lyophilized to give(1R,2R)-2-(6-(2-(4-(pyrrolidin-1-ylmethyl)phenyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (2.8 mg). ES/MS m/z 501.2 (MH⁺).

Example 209(1R,2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Step 1. Preparation of2-(4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehyde

To the reaction solid of(1R,2R)-2-(6-(2-(1-((1,3-dioxolan-2-yl)methyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(195 mg, 0.395 mmol) was added 3M HCl (6.0 ml, 18 mmol). The reactionsolution was stirred at 95° C. for 6 hours or until done by LC. Thecrude reaction mixture was lyophilized to solid and re-dissolved in 2 mlof water and 2 ml of NMP, purified on prep HPLC and lyophilized to give2-(4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehydeas TFA salt (50 mg). ES/MS m/z 468.2 (MH⁺).

Step 2. Preparation of(1R,2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of2-(4-(4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehyde(12.5 mg, 0.0267 mmol) in 0.5 ml of NMP was added pyrrolidine (19 mg,0.267 mmol) and stirred for 10 minutes. To this reaction mixture wasadded excess acetic acid (0.070 ml, 1.16 mmol) and stirred for 20minutes. To this reaction mixture was added sodium triacetoxyborohydride(13 mg, 0.0614 mmol). The reaction mixture was stirred at roomtemperature for 90 minutes. The crude reaction mixture was filtered,purified on prep HPLC and lyophilized to give(1R,2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (1.4 mg). ES/MS m/z 505.2 (MH⁺).

Example 210 Preparation ofN-(cyclohexylmethyl)-6-(pyridin-4-yloxy)benzo[d]thiazol-2-amine

To the solution ofN-(cyclohexylmethyl)-6-(pyridin-4-yloxy)benzo[d]thiazol-2-amine (20 mg,0.076 mmol, 1.0 eq) in NMP at room temperature was added cesiumcarbonate (61 mg, 0.190 mmol, 2.5 eq), 4-chloropyridine HCl (12.5 mg,0.083 mmol, 1.1 eq) and DIPEA (33 μL, 0.190 mmol, 2.5 eq) and reactionleft stirring at 80° C. for 72 hours. Thereafter, the product wasisolated by preparative HPLC and pure fraction lyophilized to give thetitle compound as TFA salt (1.4 mg). ES/MS m/z 340.1 (MH⁺).

Example 211 Preparation of4-(2-((1R,2R)-2-hydroxycyclohexylamino)-1-oxo-benzo[d]thiazol-6-yloxy)-N-methylpicolinamide

A solution of OXONE® (KHSO₅, 380 mg, mmol) in water (4 ml) was addeddropwise to a solution of4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide(25 mg, mmol) in methanol (4 ml) at rt. After stirring for 23 hours thesuspension is diluted with water (50 ml) and extracted with ethylacetate (2×10 ml). The combined organic layers were washed with brine,concentrated, and purified by prep HPLC to yield the title compound aswhite solid. Yield: 2.4 mg. ES/MS m/z 415.1 (MH⁺), Rt=1.81 min.

Example 212 Preparation of(S)—N-(1-cyclohexylethyl)-6-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

Following the procedure for Example 176 (Table 3). The reaction mixturewas heated at 110° C. for 3 hours and purified by prep HPLC to give thetitle compound. Yield: 13 mg. ES/MS m/z 448.1 (MH⁺), Rt=2.79 min.

Example 213 Preparation of(S)—N-(1-cyclohexylethyl)-6-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

Following the procedure of Example 185 (Table 3), the crude material wasfirstly purified by prep HPLC and lyophilized. The residue was dissolvedin ethyl acetate/saturated sodium bicarbonate solution (10 ml/10 ml).The separated organic layer was dried over sodium sulfate, concentratedin vacuo, and purified by prep TLC using dichloromethane/methanol(95:5). The purified product was dissolved in acetonitrile (3 ml) and 1Naqueous HCl (0.5 ml) and lyophilized to give the title compound as itsHCl salt. Yield: 11 mg. ES/MS m/z 533.1 (MH⁺), Rt=2.14 min.

Example 214 Preparation of(S)-6-(2-chloropyridin-4-yloxy)-N-(1-(ethylsulfonyl)piperidin-3-yl)benzo[d]thiazol-2-amine

Step 1. Preparation of (S)-tert-butyl3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate

To the solution of 2-chloro-6-methoxybenzo[d]thiazole (2.6 g, 13 mmol)in 25 ml of NMP was added (S)-tert-butyl3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (5 g, 25mmol) and DIPEA (2.6 ml, 15 mmol). The reaction solution was stirred at100° C. for 7 days. The crude reaction solution was mixed with ethylacetate (250 ml) and diluted aqueous sodium bicarbonate solution (80 ml)and the organic phase was separated. The separated organic layer waswashed with water (2×60 ml) and brine (60 ml), then dried over sodiumsulfate and evaporated in vacuo to give a brown oily product that waspurified by flash chromatography over silica gel with ethylacetate:hexane (35:65-50:50) to give (S)-tert-butyl3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (3.33 g,9.16 mmol) as an ivory solid. ES/MS m/z 364.2 (MH⁺). Rt=2.2 min.

Step 2. Preparation of(S)-6-methoxy-N-(piperidin-3-yl)benzo[d]thiazol-2-amine

To a solution of (S)-tert-butyl3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (3.35 g,9.22 mmol) in methanol/dioxane (3 ml/3 ml) was added slowly 4M HCl indioxane (60 ml, 240 mmol) [Caution: gas development!]. The reactionmixture was stirred 2.5 hours at ambient temperature and concentrated invacuo in order to remove methanol and half of dioaxane. The residue wassuspended in diethylether (50 ml). The solids were filtered off, washedwith diethylether (50 ml) and dried in vacuo to give(S)-6-methoxy-N-(piperidin-3-yl)benzo[d]thiazol-2-amine as itshydrochloride salt as white solid. Yield: 4.29 g. ES/MS m/z 264.1 (MH⁺),Rt=1.62 min.

Step 3. Preparation of(S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-methoxybenzo[d]thiazol-2-amine

A mixture of (S)-6-methoxy-N-(piperidin-3-yl)benzo[d]thiazol-2-aminehydrochloride salt (2.0 g, 5.95 mmol), ethylsulfonyl chloride (1.13 ml,11.91 mmol) and DIPEA (4.11 ml, 23.8 mmol) in NMP (25 ml) was heated at55° C. for 16 hours 50 min. The reaction mixture was allowed to cooldown to room temperature and diluted with water (150 ml) and ethylacetate (150 ml). After stirring vigorously for 1 hour the separatedorganic layer was washed with water (3×100 ml), saturated sodiumbicarbonate solution (3×100 ml), water (100 ml) and brine (100 ml) anddried over sodium sulfate. Concentration in vacuo and purification byflash chromatography over silica gel with ethyl acetate:hexane(20:80-100:0) provided(S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-methoxybenzo[d]thiazol-2-amineas tan solid. Yield: 1.22 g. ES/MS m/z 356.0 (MH⁺), Rt=2.12 min.

Step 4. Preparation of(S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-ol

A solution of(S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-methoxybenzo[d]thiazol-2-amine(1.22 g, 3.43 mmol) in dichloromethane (25 ml) under nitrogen atmospherewas treated with boron tribromide (1M in dichloromethane, 7.5 ml) at 0°C. Stirring was continued for 10 min at 0° C. and for 135 min at ambienttemperature. The reaction mixture was carefully diluted with water (50ml), ethyl acetate (200 ml) and treated with solid sodium bicarbonate(until no further gas development was observed). The mixture was stirreduntil phases became clear. The separated organic phase was washed withsaturated sodium bicarbonate solution (2×75 ml), water (75 ml), brine(75 ml) and dried over sodium sulfate. Concentration in vacuo affordedcrude (S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-olwhich was used in the next step without further purification. Yield:1.15 g. ES/MS m/z 342.0 (MH⁺), Rt=1.86 min.

Step 5. Preparation of(S)-6-(2-chloropyridin-4-yloxy)-N-(1-(ethylsulfonyl)piperidin-3-yl)benzo[d]thiazol-2-amine

To a mixture of(S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-ol (1.15g, 3.37 mmol) and cesium carbonate (2.20 g, 6.74 mmole) in 12 ml of NMPwas added 2-chloro-4-fluoropyridine (532 mg, 4.05 mmol). The reactionmixture was stirred at 60° C. for 17 hours. The reaction mixture wasdiluted with water (100 ml) and ethyl acetate (100 ml). The separatedorganic layer was washed with water (3×50 ml), saturated sodiumbicarbonate solution (3×50 ml), water (50 ml), brine (100 ml) and driedover sodium sulfate. Concentration in vacuo and purification by flashchromatography over silica gel with ethyl acetate:hexane (1:1 to 3:1)provided the title compound. Yield: 671 mg. ES/MS m/z 453.0 (MH⁺),Rt=2.59 min.

Example 215(1R,2R)-2-(6-(2-(3-methoxyprop-1-ynyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(2-(3-methoxyprop-1-ynyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(18.8 mg, 0.05 mmol) in 0.5 ml of DMF was added Pd(dppf)₂Cl₂ (8.2 mg,0.01 mmol), CuI (4.3 mg, 0.0225 mmol), 3-methoxyprop-1-yne (15.8 mg,0.225 mmol) and last add DIPEA (0.026 ml, 0.15 mmol). The reactionsolution was stirred at 100° C. for 90 minutes or until done by LC. Thecrude reaction mixture was filtered, purified on prep HPLC andlyophilized to give(1R,2R)-2-(6-(2-(3-methoxyprop-1-ynyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (9.2 mg). ES/MS m/z 410.1 (MH⁺).

Example 216(1R,2R)-2-(6-(2-ethynylpyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The subject compound was prepared according to the general Scheme below:

Preparation of(1R,2R)-2-(6-(2-ethynylpyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of(1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol(16 mg, 0.043 mmol) in 0.5 ml of DMF was added Pd(dppf)₂Cl₂ (8.8 mg,0.0108 mmol), CuI (4.5 mg, 0.024 mmol), ethynyltrimethylsilane (21.1 mg,0.215 mmol) and last add DIPEA (0.023 ml, 0.129 mmol). The reactionsolution was stirred at 100° C. for 90 minutes or until done by LC. Tothe crude reaction mixture a 3M NaOH solution (0.175 ml, 0.525 mmol) wasadded. The crude reaction mixture was stirred at room temperature for 30minutes or until done by LC. The thick crude reaction mixture wasneutralize with excess acetic acid (0.085, 1.41 mmol) and 0.5 ml DMF wasadded. The mixture was stirred for 5 minutes, filtered, purified on prepHPLC and lyophilized to give(1R,2R)-2-(6-(2-ethynylpyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanolas TFA salt (4.6 mg). ES/MS m/z 366.1 (MH⁺).

Example 217 Preparation of(S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

Following the procedure for Example 176. The reaction mixture was heatedat 85° C. for 18 hours and at 90° C. for 24 hour. Purification by prepHPLC gave the title compound. Yield: 2.1 mg. ES/MS m/z 527.1 (MH⁺),Rt=2.24 min.

Example 218 Preparation of(S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-(2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine

Following the procedure for Example 176. The reaction mixture was heatedat 105° C. for 18 hours and purified by prep HPLC to give the titlecompound. Yield: 9.8 mg. ES/MS m/z 531.2 (MH⁺), Rt=1.89 min.

Example 219 Preparation of(1R,2R)-2-(6-(pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol

To the reaction mixture of2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (20 mg, 0.0755mmole) in 0.5 ml of NMP was added cesium carbonate (62 mg, 0.189 mmol)and stirred at room temperature for 1-3 minutes. To this mixture wasadded additional cesium carbonate (98.5 mg, 0.302 mmol) and4-chloropyridine hydrochloride (45.3 mg, 0.302 mmol). The reactionmixture was stirred at 105-110° C. for 48 hours or until done by LC. Thecrude reaction mixture was filtered, purified on prep HPLC andlyophilized to give(1R,2R)-2-(6-(pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol asTFA salt (1.1 mg). ES/MS m/z 342.1 (MH⁺).

Compounds 1-381 in Table 3 and 1-102, 104-106, and 112-119 in Table 4were made according to the examples above, and in particular accordingto the example noted in the Ex Prep (Example Preparation) column.Compounds 103 and 107-111 can be made according to the examples above.

TABLE 3 Ex (M + H)+, Cmpd Prep Structure Name Rt (min.) 1 199

N-methyl-4-(2-(4-((4- methylpiperazin-1- yl)methyl)benzylamino)benzo[d]thiazol-6- yloxy)picolinamide 503, 1.89 2 199

N-methyl-4-(2-(3-((4- methylpiperazin-1- yl)methyl)benzylamino)benzo[d]thiazol-6- yloxy)picolinamide 503, 1.89 3 199

N-methyl-4-(2-(4-(4- methylpiperazin-1- yl)benzylamino)benzo[d]thiazol-6-yloxy)picolinamide 489, 1.98 4 200

N-methyl-4-(2-(2-(2-(4- methylpiperazin-1-yl)ethoxy)phenylamino)benzo[d] thiazol-6- yloxy)picolinamide 519, 2.20 5200

4-(2-(3-(2- (dimethylamino)ethoxy)phenyl- amino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 464, 2.18 6 200

N-methyl-4-(2-(3-(2- (piperidin-1- yl)ethoxy)phenylamino)benzo[d]thiazol-6- yloxy)picolinamide 504, 2.29 7 201

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] oxazol-6-yloxy)-N-methylpicolinamide 383, 1.96 8 201

(S)-4-(2-(1-hydroxy-3- phenylpropan-2- ylamino)benzo[d]oxazol-6-yloxy)-N-methylpicolinamide 419, 2.22 9 201

(S)-4-(2-(1- cyclohexylethylamino)benzo[d] oxazol-6-yloxy)-N-methylpicolinamide 395, 2.68 10 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N,N-dimethylpicolinamide 413.1, 1.87 11 171

N-cyclopropyl-4-(2-((1R,2R)- 2- hydroxycyclohexylamino)benzo[d]thiazol-6- yloxy)picolinamide 425.2, 2.13 12 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-(tetrahydro-2H-pyran-4- yl)picolinamide 469.2, 2.09 13 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-(1-methylpiperidin-4- yl)picolinamide 482.2, 1.85 14 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-(1-methylpiperidin-3- yl)picolinamide 482.2, 1.87 15 171

N-(2-acetamidoethyl)-4-(2- ((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6- yloxy)picolinamide 470.2, 1.86 16 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-(2-(pyrrolidin-1- yl)ethyl)picolinamide 482.2, 1.84 17 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-((tetrahydrofuran-2- yl)methyl)picolinamide 469.2, 2.16 18 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-((tetrahydro-2H-pyran-4- yl)methyl)picolinamide 483.2, 2.12 19 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-((1-methylpiperidin-4- yl)methyl)picolinamide 496.2, 1.84 20 171

N-(((S)-1-ethylpyrrolidin-2- yl)methyl)-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d] thiazol-6- yloxy)picolinamide 496.2,1.88 21 200

N-methyl-4-(2- (phenylamino)benzo[d] thiazol-6-yloxy)picolinamide 377.1,2.70 22 200

N-methyl-4-(2-(2- (trifluoromethyl)phenylamino) benzo[d]thiazol-6-yloxy)picolinamide 445.1, 2.84 23 200

4-(2-(2- bromophenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 455.0/ 457.0, 2.88 24 200

4-(2-(2- isopropylphenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 419.2, 2.82 25 200

4-(2-(2-tert- butylphenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 433.2, 2.87 26 200

N-methyl-4-(2-(2- morpholinophenylamino) benzo[d]thiazol-6-yloxy)picolinamide 462.1, 2.70 27 200

4-(2-(2- ethoxyphenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.92 28 200

N-methyl-4-(2-(2- (trifluoromethoxy)phenylamino) benzo[d]thiazol-6-yloxy)picolinamide 461.1, 3.15 29 200

N-methyl-4-(2-(2- phenoxyphenylamino)benzo[d] thiazol-6-yloxy)picolinamide 469.1, 3.29 30 200

4-(2-(2- (benzyloxy)phenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 483.2, 3.19 31 200

4-(2-(3- chlorophenylamino)benzyl[d] thiazol-6-yloxy)-N-methylpicolinamide 411.1, 3.09 32 200

4-(2-(3- methylphenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 407.1, 2.74 33 200

N-methyl-4-(2-(3-(1,1,2,2- tetrafluoroethoxy)phenyl-amino)benzo[d]thiazol-6- yloxy)picolinamide 493.1, 3.07 34 200

4-(2-(2-(1H-pyrazol-1- yl)phenylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 443.1, 2.85 35 200

N-methyl-4-(2-(3-(pyrrolidin- 1- yl)phenylamino)benzo[d]thiazol-6-yloxy)picolinamide 446.2, 2.63 36 200

N-methyl-4-(2-(3- morpholinophenylamino) benzo[d]thiazol-6-yloxy)picolinamide 462.1, 2.42 37 200

4-(2-(3- carbamoylphenylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.38 38 200

4-(2-(3-chloro-4- morpholinophenylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 496.1, 2.88 39 200

4-(2-(3-methoxy-5- (trifluoromethyl)phenylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 475.1, 3.25 40 200

4-(2-(3,5- dimethoxyphenylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 437.1, 2.79 41 200

N-methyl-4-(2-(4- morpholinophenylamino) benzo[d]thiazol-6-yloxy)picolinamide 462.2, 2.20 42 162

(R)-4-(2-(2-hydroxy-2- phenylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.13 43 162

(R)-4-(2-(1-cyclohexyl-2- hydroxyethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 427.2, 2.30 44 162

(S)-4-(2-(1-cyclohexyl-2- hydroxyethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 427.2, 2.29 45 200

N-methyl-4-(2-(2-(pyrrolidin- 1- yl)phenylamino)benzo[d]thiazol-6-yloxy)picolinamide 446.1, 2.24 46 200

N-methyl-4-(2-(2-(2- oxopyrrolidin-1- yl)phenylamino)benzo[d]thiazol-6-yloxy)picolinamide 460.1, 2.35 47 171

N-methyl-4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)picolinamide 413.2, 2.09 48 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-N-(2,2,2- trifluoroethyl)picolinamide 467.1, 2.37 49 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-N-propylpicolinamide 427.1, 2.25 50 171

N-cyclopropylmethyl)-4-(2- ((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6- yloxy)picolinamide 439.2, 2.32 51 171

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-N-isopropylpicolinamide 427.2, 2.24 52 205

N-(cyclohexylmethyl)-6-(2- (4-phenyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 482.2, 2.57 53 205

N-(cyclohexylmethyl)-6-(2- (4,5-dimethyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 434.2, 2.33 54 206

N-(cyclohexylmethyl)-6-(2- (4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 474.2, 2.87 55178

N-(cyclohexylmethyl)-6-(3- fluoropyridin-4- yloxy)benzo[d]thiazol-2-amine 358.1, 2.35 56 162

4-(2-(2-hydroxy-3- morpholinopropylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 444.2, 1.72 57 162

N-methyl-4-(2-(2- phenylpropan-2- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 419.1, 2.51 58 205

N-(cyclohexylmethyl)-6-(2- (4-methyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 420.1, 2.26 59 162

4-(2- (cyclopropylmethylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 355.1, 2.03 60 162

4-(2-(2- acetamidoethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 386.1, 1.70 61 162

N-methyl-4-(2-(2-(2- oxopyrrolidin-1- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 412.1, 1.82 62 162

N-methyl-4-(2-(2- morpholinoethylamino)benzo[d] thiazol-6-yloxy)picolinamide 414.1, 1.79 63 162

(R)-N-methyl-4-(2- ((tetrahydrofuran-2- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 385.2, 1.93 64 162

(S)-N-methyl-4-(2- ((tetrahydrofuran-2- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 385.2, 1.95 65 162

N-methyl-4-(2-(2-(pyrrolidin- 1- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 398.2, 1.83 66 162

N-methyl-4-(2-(tetrahydro- 2H-pyran-4- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 385.2, 1.88 67 162

N-methyl-4-(2-((1- methylpiperidin-4- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 412.2, 1.70 68 162

4-(2-((1-acetylpiperidin-4- yl)methylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 440.2, 1.86 69 162

4-(2-(2- hydroxyethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 345.1, 1.65 70 162

N-methyl-4-(2-(2-(1- methylpyrrolidin-2- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 412.2, 1.75 71 162

4-(2-(3- hydroxypropylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 359.1, 1.70 72 162

4-(2-(1-ethylpiperidin-3- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 412.2, 1.84 73 162

4-(2-(2- methoxyethylamino)benzo[d] thiazol-6-yl)-N- methylpicolinamide359.1, 1.83 74 162

N-methyl-4-(2-((1- methylpiperidin-3- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 412.2, 1.75 75 162

N-methyl-4-(2-(2,2,6,6- tetramethylpiperidin-4-ylamino)benzo[d]thiazol-6- yloxy)picolinamide 440.2, 1.89 76 162

(R)-4-(2-((1-ethylpyrrolidin-2- yl)methylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 412.2, 1.92 77 162

(S)-4-(2-((1-ethylpyrrolidin-2- yl)methylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 412.2, 1.92 78 162

4-(2- (isopropylamino)benzo[d] thiazol-6-yloxy)-N- methylpicolinamide343.1, 1.92 79 162

4-(2- (isobutylamino)benzo[d] thiazol-6-yloxy)-N- methylpicolinamide357.1, 2.10 80 162

4-(2- (cyclohexyl(methyl)amino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 397.2, 2.49 81 162

4-(2- (benzyl(methyl)amino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 405.1, 2.63 82 162

N-methyl-4-(2-(3- phenylpropylamino)benzo[d]thiazol-6-yloxy)picolinamide 419.2, 2.45 83 162

N-methyl-4-(2-(2- (methylsulfonyl)ethylamino) benzo[d]thiazol-6-yloxy)picolinamide 407.1, 1.85 84 162

4-(2-(4,4- difluorocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 419.2, 2.31 85 162

N-methyl-4-(2-(tetrahydro- 2H-pyran-3- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 385.1, 1.95 86 162

(R)-N-methyl-4-(2-(6- oxopiperidin-3- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 398.1, 1.76 87 162

N-methyl-4-(2-((2-oxo-1,2- dihydropyridin-4- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 408.1, 1.79 88 162

(S)-N-methyl-4-(2-(6- oxopiperidin-3- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 398.1, 1.76 89 162

N-methyl-4-(2-((6-oxo-1,6- dihydropyridin-3- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 408.1, 1.77 90 162

(R)-N-methyl-4-(2-(1,2,3,4- tetrahydronaphthalen-1-ylamino)benzo[d]thiazol-6- yloxy)picolinamide 431.2, 2.58 91 162

4-(2- (cycloheptylamino)benzo[d] thiazol-6-yloxy)-N- methylpicolinamide397.2, 2.41 92 162

(S)-N-methyl-4-(2-(1,2,3,4- tetrahydronaphthalen-1-ylamino)benzo[d]thiazol-6- yloxy)picolinamide 431.2, 2.57 93 162

N-methyl-4-(2-(2- oxoazepan-3- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 412.1, 1.95 94 162

4-(2-((2- methoxybenzyl)(methyl) amino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.2, 2.56 95 162

4-(2-(2-hydroxy-1- (tetrahydro-2H-pyran-4-yl)ethylamino)benzo[d]thiazol- 6-yloxy)-N- methylpicolinamide 429.2,1.83 96 162

4-(2-(bi(cyclohexan)-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 465.2, 3.05 97 162

4-(2-(2-hydroxy-1- (tetrahydrofuran-3- yl)ethylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 415.1, 1.79 98 189

4-(2-((1s,4s)-4- aminocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 398.1, 1.73 99 162

(R)-4-(2-(2- hydroxypropylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 359.1, 1.75 100 162

(S)-4-(2-(2- hydroxypropylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 359.1, 1.74 101 162

(R)-4-(2-(1-hydroxy-3- methylbutan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 387.2, 1.98 102 162

(S)-4-(2-(1-hydroxy-3- methylbutan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 387.2, 1.96 103 162

(S)-4-(2-(1-hydroxypropan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 359.1, 1.75 104 162

(R)-4-(2-(1-hydroxybutan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 373.1, 1.84 105 162

(S)-4-(2-(1-hydroxybutan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 373.1, 1.87 106 162

(R)-4-(2-(2-hydroxy-2- phenylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.13 107 162

4-(2-((1S,2S)-1-hydroxy-3- methoxy-1-phenylpropan-2-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 465.2, 2.21 108162

(R)-4-(2-(1-hydroxy-3- phenylpropan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.2, 2.17 109 162

(S)-4-(2-(1-hydroxy-3- phenylpropan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.2, 2.18 110 162

(R)-4-(2-(2-hydroxy-1- phenylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.15 111 162

(S)-4-(2-(2-hydroxy-1- phenylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.16 112 162

4-(2-((1R,2S)-1-hydroxy-1- phenylpropan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.2, 2.20 113 162

4-(2-((1S,2R)-1-hydroxy-1- phenylpropan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.2, 2.19 114 162

(R)-4-(2-(1-hydroxy-4- methylpentan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 401.2, 2.13 115 162

4-(2-((2S,3S)-1-hydroxy-3- methylpentan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-mehtylpicolinamide 401.2, 2.10 116 162

(R)-4-(2-(1-hydroxy-3,3- dimethylbutan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 401.2, 2.08 117 162

(S)-4-(2-(1-cyclohexyl-3- hydroxypropan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 441.2, 2.45 118 162

(S)-4-(2-(1-hydroxy-3,3- dimethylbutan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 401.2, 2.08 119 190

4-(2-((1s,4s)-4- acetamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 440.2, 1.85 120 190

4-(2-((1r,4r)-4- acetamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 440.2, 1.85 121 162

(R)-4-(2-(4-(2-amino-3- hydroxypropyl)-1H-imidazol-1-yl)benzo[d]thiazol-6-yloxy)- N-methylpicolinamide 425.2, 1.67 122 162

(S)-4-(2-(4-(2-amino-3- hydroxypropyl)-1H-imidazol-1-yl)benzo[d]thiazol-6-yloxy)- N-methylpicolinamide 425.2, 1.68 123 162

4-(2-(1-(2,5- dimethoxyphenyl)-1- hydroxypropan-2-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 495.2, 2.29 124162

4-(2-(2-hydroxy-3- phenoxypropylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 451.1, 2.26 125 162

4-(2-((1r,4r)-4- hydroxycyclohexylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 399.1, 1.83 126 162

(S)-4-(2-(1-hydroxy-4- methylpentan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 401.1, 2.14 127 162

4-(2-(2-hydroxy-3- methoxypropylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 389.1, 1.77 128 162

4-(2-((1R,2R,4S)- bicyclo[2.2.1]heptan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 395.2, 2.36 129 162

4-(2- (cyclooctylamino)benzo[d] thiazol-6-yloxy)-N- methylpicolinamide411.2, 2.60 130 162

4-(2- (isopentylamino)benzo[d] thiazol-6-yloxy)-N- methylpicolinamide371.2, 2.31 131 162

(S)-4-(2-(1- cyclohexylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 411.2, 2.59 132 191

4-(2-((1s,4s)-4- isobutyramidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-mehtylpicolinamide 468.2, 2.03 133 191

N-methyl-4-(2-((1s,4s)-4-(3- methylbutanamido)cyclo-hexylamino)benzo[d]thiazol-6- yloxy)picolinamide 482.2, 2.14 134 191

N-methyl-4-(2-((1S,4s)-4- ((R)-tetrahydrofuran-2-carboxamido)cyclohexylamino) benzo[d]thiazol-6- yloxy)picolinamide496.2, 2.01 135 191

4-(2-((1s,4s)-4- benzamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 502.2, 2.21 136 191

N-methyl-4-(2-((1R,4s)-4- ((S)-tetrahydrofuran-2-carboxamido)cyclohexylamino) benzo[d]thiazol-6- yloxy)picolinamide496.2, 2.01 137 191

N-methyl-4-(2-((1R,4s)-4- ((S)-1-methylpyrrolidine-2-carboxamido)cyclohexylamino) benzo[d]thiazol-6- yloxy)picolinamide509.3, 1.83 138 162

4-(2- (benzylamino)benzo[d]thiazol- 6-yloxy)-N- methylpicolinamide391.1, 2.35 139 162

N-methyl-4-(2-(pyridin-4- ylmethylamino)benzo[d]thiazol-6-yloxy)picolinamide 392.1, 1.78 140 162

4-(2-((1S,4R)- bicyclo[2.2.1]heptan-2- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 395.2, 2.35 141 162

4-(2-(2- (difluoromethoxy)benzylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 457.1, 2.53 142 162

4-(2-(2,6- dichlorophenethylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 473.0, 2.68 143 162

N-methyl-4-(2-(2-(tetrahydro- 2H-pyran-4- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 413.2, 2.02 144 162

4-(2-((2,3- dihydrobenzo[b][1,4]dioxin- 2-yl)methylamino)benzo[d]thiazol- 6-yloxy)-N- methylpicolinamide 449.1,2.52 145 162

(S)-4-(2-(2-hydroxy-2- phenylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 421.1, 2.13 146 162

4-(2-(2-hydroxy-1-(pyridin-3- yl)ethylamino)benzo[d]thiazol- 6-yloxy)-N-methylpicolinamide 422.1, 1.75 147 162

4-(2-((1R,2S)-2-hydroxy- 1,2,3,4- tetrahydronaphthalen-1-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 447.2, 2.25 148162

N-methyl-4-(2-(2-(pyrazin-2- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 407.1, 1.85 149 162

(R)-N-methyl-4-(2-(3- methylbutan-2- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 371.2, 2.20 150 162

(S)-N-methyl-4-(2-(3- methylbutan-2- ylamino)benzo[d]thiazol-6-yloxy)picolinamide 371.2, 2.20 151 178

6-(3-bromopyridin-4-yloxy)- N- (cyclohexylamino)benzo[d] thiazol-2-amine418.1/ 420.1, 2.48 152 180

6-(2-chloropyridin-4-yloxy)- N- (cyclohexylmethyl)benzo[d]thiazol-2-amine 374.1, 2.86 153 180

4-(2- (cyclohexylamino)benzo[d] thiazol-6- yloxy)picolinonitrile 365.1,2.74 154 162

4-(2-(1-((1R,4S)- bicyclo[2.2.1]heptan-2- yl)ethylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 423.2, 2.31 155 175

(1R,2R)-2-(6-(1-methyl- 1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.1, 1.83 156 175

(1R,2R)-2-(6-(2-(pyrazin-2- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 420.1, 1.91 157 175

(1R,2R)-2-(6-(2-(thiazol-5- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 425.0, 2.05 158 175

(1R,2R)-2-(6-(2-(1-methyl- 1H-imidazol-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.1, 1.84 159 175

(1R,2R)-2-(6-(2-(thiazol-4- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 425.0, 1.85 160 175

(1R,2R)-2-(6-(2-(thiazol-2- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 425.0, 2.28 161 188

(1R,2R)-2-(6-(2-(1,2,3,6- tetrahydropyridin-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 423.1, 1.38 162 177

(1R,2R)-2-(6-(2-(5-ethyl-4- methyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 450.1, 1.82 163 185

(S)-N-(1-cyclohexylethyl)-6- (2-(1-methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 434.1, 2.31 164 174

(1R,2R)-2-(6-(6'-(4- methylpiperazin-1-yl)-2,3'- bipyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 517.2, 1.75 165 174

(1R,2R)-2-(6-(6'-morpholino- 2,3'-bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 504.1, 1.93 166 174

(1R,2R)-2-(6-(2-(3- (morpholinomethyl)phenyl) pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 517.1, 1.78 167 174

(1R,2R)-2-(6-(2- cyclohexylpyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 422.1, 2.07 168 174

(1R,2R)-2-(6-(2-(4- (morpholinomethyl)phenyl) pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 517.2, 1.76 169 174

(1R,2R)-2-(6-(2- cyclopropylpyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 382.1, 1.84 170 174

(1R,2R)-2-(6-(6'-methoxy- 2,3'-bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 449.1, 1.98 171 174

(1R,2R)-2-(6-(2'-fluoro-2,4'- bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 437.1, 2.22 172 174

(1R,2R)-2-(6-(3'-fluoro-2'- morpholino-2,4'-bipyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 522.2, 2.17 173 174

(1R,2R)-2-(6-(6'-fluoro-2,3'- bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 437.1, 2.04 174 183

(1R,2R)-2-(6-(2-(piperidin-1- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 425.1, 1.98 175 183

(1R,2R)-2-(6-(2- morpholinopyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 427.1, 1.80 176 183

(1R,2R)-2-(6-(2-(4- methylpiperazin-1-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 440.1, 1.66 177 183

N-((R)-1-(4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin- 2-yl)pyrrolidin-3- yl)acetamide 468.1,1.78 178 183

N-((S)-1-(4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin- 2-yl)pyrrolidin-3- yl)acetamide 468.1,1.77 179 183

4-(4-(2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin- 2-yl)piperazin-2-one 440.1, 1.70 180175

(1R,2R)-2-(6-(2,2'-bipyridin- 4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 419.0, 1.87 181 175

(1R,2R)-2-(6-(2-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-5-yl)pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 490.1,2.60 182 172

(1R,2R)-2-(6-(2-(1-(2- morpholinoethyl)-1H- pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 521.1, 1.71 183 192

N-(cyclohexylmethyl)-6-(6,7- dimethoxyquinolin-4-yloxy)benzo[d]thiazol-2- amine 450.1, 2.43 184 192

(1R,2R)-2-(6-(6,7- dimethoxyquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 452.1, 2.00 185 176

(1R,2R)-2-(6-(2-(1-ethyl-1H- pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 436.0, 1.89 186 176

(1R,2R)-2-(6-(2-(1-(2- (diethylamino)ethyl)-1H- pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 507.1, 1.75 187 176

(1R,2R)-2-(6-(2-(1-(2,2- difluoroethyl)-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 472.0, 1.90 188 179

(1R,2R)-2-(6-(3-(1H-pyrazol- 4-yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 408.1, 1.70 189 179

(1R,2R)-2-(6-(3-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.1, 1.79 190 179

(1R,2R)-2-(6-(3,3'-bipyridin- 4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 419.1, 1.66 191 179

(1R,2R)-2-(6-(3-(1-methyl- 1H-pyrazol-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.1, 1.83 192 179

(1R,2R)-2-(6-(3,4'-bipyridin- 4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 419.1, 1.61 193 179

(1R,2R)-2-(6-(6'-amino-3,3'- bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 434.1, 1.60 194 179

(1R,2R)-2-(6-(6'-(4- methylpiperazin-1-yl)-3,3'- bipyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 517.2, 1.64 195 179

(1R,2R)-2-(6-(3- cyclopropylpyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 382.1, 1.97 196 174

(1R,2R)-2-(6-(2-(2- morpholinopyrimidin-5- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 505.1, 2.03 197 174

(1R,2R)-2-(6-(2-(4-(4- methylpiperazin-1- yl)phenyl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 516.1, 1.85 198 185

(S)-N-(1-cyclohexylethyl)-6- (6'-morpholino-2,3'-bipyridin-4-yloxy)benzo[d]thiazol-2- amine 516.1, 2.50 199 185

(S)-N-(1-cyclohexylethyl)-6- (6'-(4-methylpiperazin-1-yl)-2,3'-bipyridin-4- yloxy)benzo[d]thiazol-2- amine 529.2, 2.25 200 177

(1R,2R)-2-(6-(2-(4- (trifluoromethyl)-1H- imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 476.1, 2.35 201 181

6-(2-(1H-tetrazol-5- yl)pyridin-4-yloxy)-N- (cyclohexylmethyl)benzo[d]thiazol-2-amine 408.2, 2.35 202 192

N-(cyclohexylmethyl)-6-(2- methylpyridin-4- yloxy)benzo[d]thiazol-2-amine 354.2, 2.19 203 192

(1R,2R)-2-(6-(2- methylpyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 356.1, 1.73 204 192

N-(cyclohexylmethyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2- amine390.1, 2.38 205 192

(1R,2R)-2-(6-(quinolin-4- yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol392.2, 1.93 206 192

N-(cyclohexylmethyl)-6-(7- methoxyquinolin-4- yloxy)benzo[d]thiazol-2-amine 420.2, 2.49 207 192

(1R,2R)-2-(6-(7- methoxyquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 422.1, 2.03 208 192

N-(cyclohexylmethyl)-6-(6- fluoroquinolin-4- yloxy)benzo[d]thiazol-2-amine 408.2, 2.45 209 192

(1R,2R)-2-(6-(3- fluoropyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 360.1, 1.83 210 192

N-(cyclohexylmethyl)-6-(8- methoxyquinolin-4- yloxy)benzo[d]thiazol-2-amine 420.2, 2.46 211 192

N-(cyclohexylmethyl)-6-(6,7- difluoroquinolin-4-yloxy)benzo[d]thiazol-2- amine 426.2, 2.61 212 192

(1R,2R)-2-(6-(6- fluoroquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 410.1, 1.98 213 192

(1R,2R)-2-(6-(8- methoxyquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 422.1, 1.96 214 192

(1R,2R)-2-(6-(6,7- difluoroquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 428.1, 2.08 215 192

N-(cyclohexylmethyl)-6-(6- methoxyquinolin-4- yloxy)benzo[d]thiazol-2-amine 420.2, 2.47 216 192

(1R,2R)-2-(6-(6- methoxyquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 422.1, 1.98 217 192

4-(2-((1R,6S)-6- carbamoylcyclohex-3- enylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 424.1, 1.86 218 192

4-(2-((1R,6R)-6- carbamoylcyclohex-3- enylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 424.1, 1.90 219 192

4-(2- (cyclohexylmethylamino) benzo[d]thiazol-6-yloxy)quinolin-6-carbonitrile 415.1, 2.50 220 192

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)quinolin-6-carbonitrile 417.1, 1.99 221 192

4-(2- (cyclohexylmethylamino) benzo[d]thiazol-6-yloxy)quinoline-7-carbonitrile 415.1, 2.52 222 192

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)quinoline-7-carbonitrile 417.1, 1.98 223 162

4-(2-(2-fluoro-6- methoxybenzylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 439.1, 2.40 224 178

(1R,2R)-2-(6-(3- bromopyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 420.1/ 422.0, 1.81 225 173

(1R,2R)-2-(6-(2- chloropyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 376.1, 2.13 226 173

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)picolinonitrile 367.1, 2.03 227 192

N-(cyclohexylmethyl)-6-(7- fluoroquinolin-4- yloxy)benzo[d]thiazol-2-amine 408.1, 2.44 228 192

N-(cyclohexylmethyl)-6-(7- (trifluoromethoxy)quinolin-4-yloxy)benzo[d]thiazol-2- amine 474.1, 2.76 229 192

(1R,2R)-2-(6-(7- fluoroquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 410.1, 1.95 230 192

(1R,2R)-2-(6-(7- (trifluoromethoxy)quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 476.1, 2.25 231 177

(1R,2R)-2-(6-(2-(4-methyl- 1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.1, 1.88 232 177

(1R,2R)-2-(6-(2-(4,5- dimethyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 436.1, 1.93 233 182

(1S,2S)-3-methoxy-1- phenyl-2-(6-(quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)propan-1-ol 458.1, 2.18 234 182

(2S,3S)-3-methyl-2-(6- (quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)pentan-1-ol 394.2, 2.08 235 182

(S)-2-phenyl-2-(6-(quinolin- 4-yloxy)benzo[d]thiazol-2- ylamino)ethanol414.1, 2.11 236 182

(S)-2-cyclohexyl-2-(6- (quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)ethanol 420.2, 2.21 237 182

(1R,2S)-1-(6-(quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)-2,3-dihydro-1H- inden-2-ol 426.1, 2.20 238 182

(S)-4-methyl-2-(6-(quinolin- 4-yloxy)benzo[d]thiazol-2-ylamino)pentan-1-ol 394.2, 2.09 239 182

(1S,2R)-1-(6-(quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)-2,3-dihydro-1H- inden-2-ol 426.1, 2.20 240 182

(R)-2-cyclohexyl-2-(6- (quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)ethanol 420.2, 2.21 241 182

(S)-N-(1-cyclohexylethyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2- amine404.1, 2.48 242 182

(S)-3-phenyl-2-(6-q(quinolin- 4-yloxy)benzo[d]thiazol-2-ylamino)propan-2-ol 428.0, 2.13 243 182

(R)-N-(1-cyclohexylethyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2- amine404.1, 2.48 244 182

(S)-3-methyl-2-(6-(quinolin- 4-yloxy)benzo[d]thiazol-2-ylamino)butan-1-ol 380.1, 1.95 245 182

(R)-4-methyl-2-(6-(quinolin- 4-yloxy)benzo[d]thiazol-2-ylamino)pentan-1-ol 394.2, 2.09 246 182

N-(2- (difluoromethoxy)benzyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2-amine 450.1, 2.47 247 182

N-cycloheptyl-6-(quinolin-4- yloxy)benzo[d]thiazol-2- amine 390.1, 2.36248 182

(S)-3,3-dimethyl-2-(6- (quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)butan-1-ol 394.1, 2.05 249 182

(S)-6-(quinolin-4-yloxy)-N- (1,2,3,4- tetrahydronaphthalen-1-yl)benzo[d]thiazol-2-amine 424.1, 2.54 250 182

(S)-3-cyclohexyl-2-(6- (quinolin-4- yloxy)benzo[d]thiazol-2-ylamino)propan-2-ol 434.2, 2.37 251 182

N-((1R,2R,4S)- bicyclo[2.2.1]heptan-2-yl)-6- (quinolin-4-yloxy)benzo[d]thiazol-2- amine 388.1, 2.29 252 182

6-(quinolin-4-yloxy)-N-(2- (tetrahydro-2H-pyran-4-yl)ethyl)benzo[d]thiazol-2- amine 406.1, 2.00 253 182

N-isopentyl-6-(quinolin-4- yloxy)benzo[d]thiazol-2- amine 364.1, 2.24254 182

N-(pyridin-3-ylmethyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2- amine385.1, 1.78 255 182

N-(2-morpholinoethyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2- amine407.1, 1.77 256 182

N-cyclohexyl-6-(quinolin-4- yloxy)benzo[d]thiazol-2- amine 376.11, 2.21257 182

N-(2-methoxybenzyl)-6- (quinolin-4- yloxy)benzo[d]thiazol-2- amine414.1, 2.29 258 177

(1R,2R)-2-(6-(2-(4,5,6,7- tetrahydro-1H- benzo[d]imidazol-2-yl)pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 462.2, 2.03259 176

(1R,2R)-2-(6-(2-(1-(2- fluoroethyl)-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 454.2, 1.89 260 176

(1R,2R)-2-(6-(2-(1-(2- methoxyethyl)-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 466.2, 1.89 261 174

(1R,2R)-2-(6-(6'-amino-2,3'- bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 434.2, 1.78 262 187

(1R,2R)-2-(6-(2-(1H- imidazol-1-yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 408.2, 1.85 263 192

(1R,2R)-2-(6-(8- fluoroquinolin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 410.1, 1.95 264 184

(S)-6-(2-chloropyridin-4- yloxy)-N-(1- cyclohexylethyl)benzo[d]thiazol-2-amine 388.1, 2.95 265 174

(1R,2R)-2-(6-(2-(1-methyl- 1H-pyrazol-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.1, 1.93 266 177

(1R,2R)-2-(6-(2-(4,5-diethyl- 1H-imidazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 464.2, 2.10 267 177

(1R,2R)-2-(6-(2-(5-methyl-4- propyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 464.2, 2.10 268 186

(S)-N-(1-cyclohexylethyl)-6- (2-(4-methyl-1H-imidazol-2- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 434.2, 2.35 269 186

(S)-N-(1-cyclohexylethyl)-6- (2-(4,5-dimethyl-1H-imidazol-2-yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 448.2, 2.43 270186

(S)-N-(1-cyclohexylethyl)-6- (2-(4-ethyl-5-methyl-1H-imidazol-2-yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 462.2, 2.49 271186

(S)-N-(1-cyclohexylethyl)-6- (2-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2- yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 474.2,2.54 272 186

(S)-N-(1-cyclohexylethyl)-6- (2-(4,5-diethyl-1H-imidazol-2-yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 476.2, 2.62 273 185

(S)-N-(1-cyclohexylethyl)-6- (2-(1-propyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 462.2, 2.53 274 185

(S)-6-(2,3'-bipyridin-4-yloxy)- N-(1- cyclohexylethyl)benzo[d]thiazol-2-amine 431.2, 2.35 275 185

(S)-6-(2,4'-bipyridin-4-yloxy)- N-(1- cyclohexylethyl)benzo[d]thiazol-2-amine 431.2, 2.35 276 185

(S)-6-(6'-amino-2,3'- bipyridin-4-yloxy)-N-(1- cyclohexylethyl)benzo[d]thiazol-2-amine 446.1, 2.25 277 185

(S)-N-(1-cyclohexylethyl)-6- (2-(1-methyl-1H-pyrazol-5- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 434.2, 2.58 278 185

(S)-6-(2-(1H-pyrrolo[2,3- b]pyridin-5-yl)pyridin-4- yloxy)-N-(1-cyclohexylethyl)benzo[d] thiazol-2-amine 470.2, 2.46 279 185

(S)-N-(1-cyclohexylethyl)-6- (6'-methoxy-2,3'-bipyridin-4-yloxy)benzo[d]thiazol-2- amine 461.2, 2.58 280 174

(1R,2R)-2-(6-(2,4'-bipyridin- 4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 419.0, 1.68 281 174

(1R,2R)-2-(6-(2-(1-propyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 450.0, 2.02 282 174

(1R,2R)-2-(6-(6'-amino-5'- (trifluoromethyl)-2,3'- bipyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 502.0, 2.02 283 174

(1R,2R)-2-(6-(2-(1,3,5- trimethyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 450.0, 1.86 284 174

(1R,2R)-2-(6-(2-(1H- pyrrolo[2,3-b]pyridin-5- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 458.0, 1.91 285 174

(1R,2R)-2-(6-(2-(pyrimidin-5- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 420.1, 1.90 286 174

(1R,2R)-2-(6-(2-(2- (dimethylamino)pyrimidin-5- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 463.1, 1.96 287 174

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-2,3'-bipyridine-6'-carbonitrile 444.0, 2.18 288 174

(1R,2R)-2-(6-(2-(4- fluorophenyl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 436.0, 2.06 289 195

(S)-4-(2-(1- cyclohexylethylamino)benzo[d] thiazol-6-yloxy)-N',N'-dimethylpicolinohydrazide 440.1, 2.33 290 162

4-(2-(2- cyclopropylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 369.0, 2.03 291 195

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylnicotinamide 399.1, 1.72 292 162

4-(2-((1S,2R)-2- aminocyclohexylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 398.1, 1.79 293 162

4-(2-(3- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 399.1, 1.76 294 162

4-(2-(3- aminocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 398.1, 1.65 295 163

4-(2-((1S,2R)-2- acetamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 440.2, 1.96 296 163

4-(2-(3- acetamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 440.2, 1.87 297 163

4-(2-((1R,2R)-2- aminocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 398.2, 1.79 298 163

4-(2-((1R,2R)-2- acetamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 440.2, 1.84 299 162

4-(2-((1R,2R)-2- (hydroxymethyl)cyclohexyl- amino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 413.1, 1.92 300 164

N-methyl-4-(2-((1S,2R)-2- (methylsulfonylamido)cyclo-hexylamino)benzo[d]thiazol-6- yloxy)picolinamide 476.1, 2.05 301 167

4-(2-((1S,2R)-2-(3- isopropylureido)cyclohexyl- amino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 483.2, 2.0 302 165

(R)-4-(2-(1-acetylpiperidin-3- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 426.2, 1.91 303 165

(R)-4-(2-(1-acetylpyrrolidin- 3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 412.2, 1.84 304 165

(S)-4-(2-(1-acetylpiperidin-3- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 426.2, 1.91 305 165

(S)-4-(2-(1-acetylpyrrolidin- 3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 412.21, 1.84 306 165

4-(2-((1-acetylpiperidin-3- yl)methylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 440.1, 2.04 307 165

4-(2-(1-acetylpiperidin-4- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 426.2, 1.85 308 165

N-methyl-4-(2-((1- (methylsulfonyl)piperidin-3- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 476.1, 1.96 309 166

N-methyl-4-(2-((1S,2R)-2- ((R)-tetrahydrofuran-2-carboxamido)cyclohexylamino) benzo[d]thiazol-6- yloxy)picolinamide496.2, 2.13 310 166

4-(2-((1S,2R)-2- isobutyramidocyclohexyl-amino)benzo[d]thiazol-6-yloxy)- N-methylpicolinamide 468.2, 2.14 311 166

N-methyl-4-(2-((1S,2R)-2-(3- methylbutyanamido)cyclo-hexylamino)benzo[d]thiazol-6- yloxy)picolinamide 482.2, 2.28 312 166

4-(2-((1S,2R)-2- benzamidocyclohexylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 502.2, 2.22 313 166

N-methyl-4-(2-((1S,2R)-2- ((S)-1-methylpyrrolidine-2-carboxamido)cyclohexylamino) benzo[d]thiazol-6- yloxy)picolinamide509.2, 1.82 314 162

N-methyl-4-(2-(2-(pyridin-2- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 406.1, 1.67 315 162

N-methyl-4-(2-(2-(pyridin-3- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 406.1, 1.63 316 162

N-methyl-4-(2-(2-(pyridin-4- yl)ethylamino)benzo[d]thiazol-6-yloxy)picolinamide 406.1, 1.63 317 162

4-(2-(2- methoxyphenylethylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.1, 2.29 318 162

N-methyl-4-(2-((1S,2S)-2- phenylcyclopropylamino) benzo[d]thiazol-6-yloxy)picolinamide 417.1, 2.51 319 162

4-(2-(2- chlorophenylethylamino)benzo[d] thiazol-6-yloxy)-N-methylpicolinamide 439.1, 2.4 320 162

4-(2-((1S,2S)-2- hydroxycyclopentylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 385.1, 1.74 321 162

4-(2-((1S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 433.1, 2.08 322162

4-(2-((1S,2R)-2- hydroxycyclopentylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 385.1, 1.75 323 162

4-(2-((1R,2S)-2-hydroxy-2,3- dihydro-1H-inden-1-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 433.1, 2.08 324162

4-(2-((1R,2R)-2- hydroxycyclopentylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 385.1, 1.75 325 162

4-(2-((1S,3R,4R)-3- (hydroxymethyl)bicyclo[2.2.1] heptan-2-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 425.1, 1.92 326164

N-methyl-4-(2-((1R,2R)-2- (methylsulfonamido)cyclo-hexylamino)benzo[d]thiazol-6- yloxy)picolinamide 476.1, 1.87 327 166

4-(2-((1R,2R)-2- isobutyramidocyclohexyl-amino)benzo[d]thiazol-6-yloxy)- N-methylpicolinamide 468.1, 2.02 328 162

(S)-4-(2-(1-(2- methoxyphenyl)ethylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 435.1, 2.32 329 162

(R)-N-methyl-4-(2-(1,2,3,4- tetrahydronaphthalen-2-ylamino)benzo[d]thiazol-6- yloxy)picolinamide 431.1, 2.55 330 164

N-mehtyl-4-(2-((1S,2S)-2- (methylsulfonamido)cyclo-hexylamino)benzo[d]thiazol-6- yloxy)picolinamide 476.1, 1.87 331 164

(S)-N-methyl-4-(2-(1- (methylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6- yloxy)picolinamide 462.1, 1.90 332 162

(S)-N-methyl-4-(2-(piperidin- 3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide 384.1, 1.65 333 167

(S)-4-(2-(1- (isopropylcarbamoyl)piper- idin-3-ylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 469.2, 1.94 334 166

(S)-4-(2-(1- isobutyrylpiperidin-3- ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 454.2, 1.99 335 166

(S)-4-(2-(1- (cyclopentanecarbonyl)piper- idin-3-ylamino)benzo[d]thiazol-6- yloxy)-N-methylpicolinamide 480.2, 2.2 336166

(S)-4-(2-(1-benzoylpiperidin- 3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 488.2, 2.09 337 166

4-(2-((1- (isopropylcarbamoyl)piper- idin-3- yl)methylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 483.2, 2.09 338 170

N-(cyclohexylmethyl)-6-(2- (methylamino)pyridin-4-yloxy)benzo[d]thiazol-2- amine 369.1, 2.09 339 170

N-(cyclohexylmethyl)-6-(2- (ethylamino)pyridin-4-yloxy)benzo[d]thiazol-2- amine 383.1, 2.33 340 174

N-(cyclohexylmethyl)-6-(2- (1-methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 420.2, 2.13 341 174

6-(2-(1H-pyrazol-4-yl)pyridin- 4-yloxy)-N- (cyclohexylmethyl)benzo[d]thiazol-2-amine 406.1, 2.12 342 175

N-(cyclohexylmethyl)-6-(2- (oxazol-2-yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 407.1, 2.36 343 170

N-(cyclohexylmethyl)-6-(2- (2- methoxyethylamino)pyridin-4-yloxy)benzo[d]thiazol-2- amine 413.2, 2.16 344 174

(1R,2R)-2-(6-(2-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 422.2, 1.68 345 174

(1R,2R)-2-(6-(2,3'-bipyridin- 4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 419.1, 1.69 346 174

(1R,2R)-2-(6-(2-(2- aminopyrimidin-5-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 435.2, 1.61 347 168

(R)-2-cyclohexyl-2-(6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)ethanol 450.2, 1.96 348 168

(1R,2S)-1-(6-(2-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)-2,3-dihydro-1H- inden-2-ol 456.1, 1.94349 168

(2S,3S)-3-methyl-2-(6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)pentan-1-ol 424.2, 1.83 350 168

(1S,2R)-1-(6-(2-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)-2,3-dihydro-1H- inden-2-ol 456.1, 1.95351 168

(S)-2-(6-(2-(1-methyl-1H- pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)-3-phenylpropan-1- ol 458.1, 1.89 352168

(S)-3-methyl-2-(6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)butan-1-ol 410.1, 1.70 353 168

(S)-2-cyclohexyl-2-(6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)ethanol 450.1, 1.97 354 168

(R)-N-(1-cyclohexylethyl)-6- (2-(1-methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 434.1, 2.21 355 168

(R)-4-methyl-2-(6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)pentan-1-ol 423.1, 1.85 356 168

N-(2- (difluoromethoxy)benzyl)-6- (2-(1-methyl-1H-pyrazol-4-yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 480.1, 2.20 357 168

(S)-2-(6-(2-(1-methyl-1H- pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)-1-phenylethanol 444.1, 1.85 358 168

(S)-4-methyl-2-(6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)pentan-1-ol 424.1, 1.85 359 174

(1R,2R)-2-(6-(2-(1-isobutyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- ylamino)cyclohexanol 464.4, 1.95 360 174

(1R,2R)-2-(6-(2-(1H-pyrazol- 4-yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 408.1, 1.63 361 168

6-(2-(1-methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)-N-(2-(tetrahydro-2H-pyran-4- yl)ethyl)benzo[d]thiazol-2- amine 436.2, 1.74362 168

(S)-6-(2-(1-methyl-1H- pyrazol-4-yl)pyridin-4-yloxy)- N-(1,2,3,4-tetrahydronaphthalen-1- yl)benzo[d]thiazol-2-amine 454.2, 2.25 363 168

(R)-6-(2-(1-methyl-1H- pyrazol-4-yl)pyridin-4-yloxy)- N-(1,2,3,4-tetrahydronaphthalen-1- yl)benzo[d]thiazol-2-amine 454.2, 2.24 364 168

N-cycloheptyl-6-(2-(1- methyl-1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 420.2, 2.08 365 168

N-isopentyl-6-(2-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2- amine 394.2, 1.98 366 168

(S)-6-(2-(1-methyl-1H- pyrazol-5-yl)pyridin-4-yloxy)- N-(1,2,3,4-tetrahydronaphthalen-2- yl)benzo[d]thiazol-2-amine 454.2, 2.22 367 169

(S)-4-(2-(1- (cyclopropylsulfonyl)piperidin- 3-ylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 488.0, 2.17 368 170

(1R,2R)-2-(6-(2- (methylamino)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 371.1, 1.79 369 170

(1R,2R)-2-(6-(2- (ethylamino)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 385.1, 1.74 370 162

N-methyl-4-(2-((tetrahydro- 2H-pyran-2- yl)methylamino)benzo[d]thiazol-6-yloxy)picolinamide 399.1, 2.16 371 175

(1R,2R)-2-(6-(2-(furan-2- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 4408.1, 1.94 372 175

(1R,2R)-2-(6-(2-(oxazol-2- yl)pyridin-4- yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol 409.1, 1.98 373 169

(S)-N-(1- (cyclopropylsulfonyl)piperidin- 3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4- yloxy)benzo[d]thiazol-2- amine 511.2, 2.0 374193

4-(2- (cyclohexylmethylamino)-4- methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide 411; 2.81 375 194

4-(4-chloro-2- (cyclohexylmethylamino) benzo[d]thiazol-6-yloxy)-N-methylpicolinamide 431; 3.31 376 195

4-(7-bromo-2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 479, 2.37 377 196

4-(2-((1R,2R)-2- hydroxycyclohexylamino)-7- methylbenzo[d]thiazol-6-yloxy)-N-methylpicolinamide 413, 2.09 378 197

4-(7-chloro-2-((1R,2R)-2- hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N- methylpicolinamide 433, 2.33 379 198

4-(2- (cyclohexylmethylamino)-5- fluorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide 415, 2.81 380 203

4-(2- (cyclohexylmethylamino) benzo[d]thiazol-6-yloxy)-N-isobutoxypicolinamide 455.1, 2.90 381 204

4-(2-((1R,2R)-2- hydroxycyclohexylamino) benzo[d]thiazol-6-yloxy)-N-isobutoxypicolinamide 457.0, 2.35

TABLE 4 (M + H)+, Ex Rt Cmpd Prep Structure Name (min.) 1 168

6-(2-(1-methyl-1H- pyrazol-4- yl)pyridin-4- yloxy)-N-(4-(4-methylpiperazin-1- yl)benzyl)benzo [d]thiazol-2-amine 512.2, 1.79 2 199

N-methyl-4- (2-(3-(4- methylpiperazin-1- yl)propylamino) benzo[d]thiazol-6-yloxy) picolinamide 441.0; 1.66 3 207

(1R,2R)-2-(6-(2′- morpholino-2,4- bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino) cyclohexanol 504.1, 1.99 4 207

(1R,2R)-2-(6-(2′-(4- methylpiperazin- 1-yl)-2,4′- bipyridin-4-yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 517.2, 1.86 5 207

1-(4-(2-((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)-2,4′- bipyridin-2′-yl) piperidin-4-ol 518.2, 1.93 6 207

(1R,2R)-2-(6- (2′-((R)-3- (dimethylamino) pyrrolidin-1-yl)-2,4′-bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 531.2,1.85 7 207

4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)-2,4′- bipyridin-2′-yl) piperazin-2-one 517.2, 1.89 8 207

(1R,2R)-2- (6-(2′-((S)-3- (dimethylamino) pyrrolidin-1-yl)-2,4′-bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol531.2, 1.85 9 207

(1R,2R)-2- (6-(2-(4- (dimethylamino) piperidin-1- yl)-2,4′-bipyridin-4-yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 545.2, 1.87 10 207

(1R,2R)-2-(6- (2′-(pyrrolidin-1- yl)-2,4′-bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino) cyclohexanol 488.2, 2.05 11 207

(1R,2R)-2-(6-(2′- (4-fluoropiperidin- 1-yl)-2,4′- yloxy)benzo[d]thiazol-2- bipyridin-4-ylamino) cyclohexanol 520.2, 2.10 12 207

(1R,2R)-2-(6-(2′- (dimethylamino)- 2,4′-bipyridin- 4-yloxybenzo[d]thiazol-2-ylamino) cyclohexanol 462.1, 1.95 13 207

1-(4-(2-((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)-2,3′- bipyridin-6′-yl) piperidin-4-ol 518.2, 1.88 14 207

(1R,2R)-2- (6-(6′-((R)-3- (dimethylamino) pyrrolidin-1-yl)-2,3′-bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol531.2, 1.80 15 207

4-(4-(2-((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)-2,3′- bipyridin-6′-yl) piperazin-2-one 517.2, 1.86 16 207

(1R,2R)-2- (6-(6′-((S)-3- (dimethylamino) pyrrolidin-1-yl)-2,3′-bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol531.2, 1.80 17 207

(1R,2R)-2- (6-(6′-(4- (dimethylamino) piperidin-1- yl)-2,3-bipyridin-4-yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 545.2, 1.83 18 207

(1R,2R)-2-(6- (6′-(pyrrolidin- 1-yl)-2,3′-bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino) cyclohexanol 488.1, 1.95 19 207

(1R,2R)-2- (6-(6′-(4- fluoropiperidin- 1-yl)-2,3′-bipyridin-4-yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 520.2, 2.10 20 207

(1R,2R)- 2-(6-(6′- (dimethylamino)-2,3′- bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino) cyclohexanol 462.1, 1.88 21 207

(1R,2R)-2-(6- (6′-(piperidin-1- yl)-2,3′-bipyridin-4- yloxy)benzo[d]thiazol-2-ylamino) cyclohexanol 502.2, 2.08 22 207

(1R,2R)-2- (6-(6′-(4- isopropylpiperazin- 1-yl)-2,3′- bipyridin-4-yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 545.2, 1.87 23 210

N- (cyclohexylmethyl)-6- (pyridin-4- yloxy)benzo[d] thiazol-2-amine340.1, 2.11 24 169

(S)-6-(2-(1- methyl-1H-pyrazol- 4-yl)pyridin-4- yloxy)-N-(1-(methylsulfonyl) piperidin-3- yl)benzo[d] thiazol-2-amine 485.0, 1.91 25169

(S)-N-(1- (ethylsulfonyl) piperidin-3-yl)- 6-(2-(1-methyl- 1H-pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2-amine 499.0, 1.98 26 179

4-fluoro-3-(4- (2-((1R,2R)-2- hydroxycyclo- hexylamino)benzo[d]thiazol-6- yloxy)pyridin- 2-yl)-N,N- dimethylbenzamide 507.1,1.95 27 179

3-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)-N,N- dimethylbenzamide 489.1, 1.95 28 179

(3-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)phenyl) (pyrrolidin-1- yl)methanone 515.2, 2.05 29179

(3-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin-2- yl)phenyl) (morpholino) methanone 531.2, 1.95 30 179

(3-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)phenyl)(4- methylpiperazin-1- yl)methanone 544.1,1.72 31 179

(4-(2-((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)-2,3′- bipyridin-5- yl)(morpholino) methanone 532.1, 1.86 32 179

4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)-N,N- dimethylbenzamide 489.2, 1.95 33 179

(4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)phenyl) (pyrrolidin-1- yl)methanone 515.2, 2.05 34179

(4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin-2- yl)phenyl) (morpholino) methanone 531.2, 1.95 35 179

(4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)phenyl)(4- methylpiperazin-1- yl)methanone 544.2,1.80 36 179

4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)-N-(2- hydroxyethyl) benzamide 505.2, 1.84 37 179

4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)benzamide 461.1, 1.85 38 179

(1R,2R)-2- (6-(2-(2-(4- methylpiperazin-1- yl)pyrimidin-5- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 518.2, 1.81 39 185

(1R,2R)-2-(6- (2-(1H-pyrazol- 5-yl)pyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 408.0, 1.78 40 185

3-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)-N-(2- hydroxyethyl) benzamide 505.1, 1.86 41 177

(1R,2R)-2- (6-(2-(4-(4- methyl-1H- imidazol-2- yl)phenyl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 498.1, 1.89 42 177

(1R,2R)-2- (6-(2-(4-(4,5- dimethyl-1H- imidazol-2- yl)phenyl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 512.2, 1.93 43 180

(S)-4-(2-(1- cyclohexylethylamino) benzo[d]thiazol-6-yloxy)picolinonitrile 379.1, 2.94 44 177

(1R,2R)-2- (6-(2-(4-(4- (trifluoromethyl)-1H- imidazol-2-yl)phenyl)pyridin- 4-yloxy)benzo [d]thiazol-2- ylamino) cyclohexanol 552.1,2.26 45 208

(1R,2R)-2-(6-(2-(4- (pyrrolidin-1- ylmethyl)phenyl) pyridin- yloxy)benzo[d]thiazol-2- ylamino) cyclohexanol 501.2, 1.85 46 208

(1R,2R)-2- (6-(2-(4-((4- methylpiperazin-1- yl)methyl)phenyl) pyridin-4-yloxy)benzo [d]thiazol-2- ylamino) cyclohexanol 530.2, 1.82 47 211

4-(2-((1R,2R)-2- hydroxycyclo- hexylamino)-1- oxo-benzo[d]thiazol-6-yloxy)- N- methylpicolinamide 415.1, 1.81 48 168

((1S,2S)-2- (6-(2-(1-methyl- 1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)cyclohexyl) methanol 436.0, 1.90 49 179

(1R,2S)-1-(6- (2,3′-bipyridin- 4-yloxy)benzo[d] thiazol-2- ylamino)-2,3-dihydro-1H- inden-2-ol 453.0, 2.09 50 179

(1R,2S)-1- (6-(6′-amino-2,3′- bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino)-2,3- dihydro-1H- inden-2-ol 468.0, 2.02 51 179

(1R,2S)-1- (6-(6′-(4- methylpiperazin- 1-yl)-2,3′- bipyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 551.1,1.96 52 179

(1R,2S)-1-(6- (6′-morpholino- 2,3′-bipyridin-4- yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 538.1, 2.18 53 179

(1R,2S)-1-(6- (2,4′-bipyridin- 4-yloxy)benzo[d] thiazol-2- ylamino)-2,3-dihydro-1H- inden-2-ol 453.1, 2.15 54 179

(1R,2S)-1-(6- (2-(1H-pyrazol- 4-yl)pyridin-4- yloxy)benzo[d] thiazol-2-ylamino)-2,3- dihydro-1H- inden-2-ol 442.0, 2.01 55 179

(1R,2S)-1-(6- (2-(1-propyl- 1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 484.1, 2.25 56 179

(1R,2S)-1- (6-(2-(1-(2- morpholinoethyl)- 1H- pyrazol-4-yl) pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 555.1,1.92 57 176

(1R,2S)-1-(6- (2-(1-ethyl-1H- pyrazol-4-yl) pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 470.0, 2.16 58 176

(1R,2S)-1- (6-(2-(1-(2- methoxyethyl)- 1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 500.0,2.12 59 176

(1R,2S)-1-(6-(2-(1- (2-(diethylamino) ethyl)-1H-pyrazol- 4-yl)pyridin-4-yloxy)benzo[d] thiazol-2-ylamino)- 2,3-dihydro-1H- inden-2-ol 541.1,1.97 60 179

(4-(4-(2-((1R,2S)-2- hydroxy-2,3- dihydro-1H-inden- 1-ylamino)benzo[d]thiazol-6- yloxy)pyridin-2- yl)phenyl) (pyrrolidin-1- yl)methanone549.2, 2.25 61 212

(S)-N-(1- cyclohexylethyl)-6- (2-(1-ethyl-1H- pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2-amine 448.1, 2.79 62 212

(S)-N-(1- cyclohexylethyl)-6- (2-(1-(2,2- difluoroethyl)-1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d] thiazol-2-amine 484.1, 2.44 63212

(S)-N-(1- cyclohexylethyl)-6- (2-(1-(2- (diethylamino)ethyl)-1H-pyrazol-4- yl)pyridin-4- yloxy)benzo[d] thiazol-2-amine 519.2, 2.1864 212

(S)-N-(1- cyclohexylethyl)-6- (2-(1-(2- methoxyethyl)-1H- pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2-amine 478.1, 2.37 65 212

(S)-N-(1- cyclohexylethyl)-6- (2-(l-(2- fluoroethyl)-1H- pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2-amine 466.1, 2.38 66 213

(S)-N-(1- cyclohexylethyl)-6- (2-(1-(2- morpholinoethyl)- 1H-pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2-amine 533.1, 2.14 min 67 176

(1R,2S)-1- (6-(2-(1-(2- fluoroethyl)-1H- pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 488.1,2.17 68 176

(1R,2S)-1- (6-(2-(1-(2,2- difluoroethyl)- 1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 506.1,2.25 69 179

(1R,2S)-1- (6-(2′-(4- methylpiperazin- 1-yl)-2,4′- bipyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 551.2,2.09 70 207

(1R,2S)-1- (6-(6-((S)-3- (dimethylamino) pyrrolidin-1-yl)-2,3′-bipyridin-4- yloxy)benzo[d] thiazol-2- ylamino)-2,3-dihydro-1H- inden-2-ol 565.2. 2.02 71 179

4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)pyridin- 2(1H)-one 435.1, 1.82 72 179

(1R,2R)-2-(6- (5′-fluoro-2,3′- bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 437.1, 2.07 73 179

(1R,2R)-2- (6-(5′-methoxy- 2,3′-bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol 449.1, 2.00 74 179

5-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)pyridin- 2(1H)-one 435.1, 1.77 75 173

(1R,2S)-1-(6-(2- chloropyridin-4- yloxy)benzo[d] thiazol-2-ylamino)-2,3- dihydro-1H- inden-2-ol 410.0, 2.63 76 176

(R)-4-methyl-2- (6-(2-(1-(2- morpholinoethyl)- 1H- pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2- ylamino) pentan-1-ol 523.1, 1.84 77176

(R)-4-methyl- 2-(6-(2-(1- propyl-1H- pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino) pentan-1-ol 452.1, 2.31 78 176

(R)-4-methyl- 2-(6-(6′-(4- bipyridin-4- methylpiperazin- 1-yl)-2,3′-yloxy)benzo[d] thiazol-2- ylamino) pentan-1-ol 519.1, 1.85 79 176

(R)-2-(6-(6′- amino-2,3′- bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino)-4- methylpentan-1- ol 436.0, 1.94 80 176

(R)-2-(6-(2-(1-(2- (diethylamino) ethyl)-1H- pyrazol-4-yl) pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-4- methylpentan-1- ol 509.1; 1.89 81176

(R)-2-(6- (2-(1-(2,2- difluoroethyl)- 1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-4- methylpentan-1- ol 474.0, 2.07 82176

(R)-2-(6-(2-(1-(2- methoxyethyl)- 1H-pyrazol-4- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-4- methylpentan-1- ol 468.1, 2.00 83176

(R)-2-(6- (2-(1-ethyl-1H- pyrazol-4-yl) pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)-4- methylpentan-1- ol 438.1, 2.13 84 176

(R)-2-(6-(2-(1- (2-fluoroethyl)- 1H-pyrazol-4-yl) pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-4- methylpentan-1- ol 456.3, 2.11 8516

4-(2-((1S,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol- 6-yloxy)-N-methylpicolinamide; 4-(2-((1R,2S)-2- hydroxycyclo- hexylamino)benzo[d]thiazol- 6-yloxy)-N- methylpicolinamide 399.1, 2.07 86 177

(R)-2-(6- (2-(4-ethyl-5- methyl-1H- imidazol-2- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-4- methylpentan-1- ol 452.1, 2.18 87209

(1R,2R)-2-(6- (2-(1-(2-(4- methylpiperazin- 1-yl)ethyl)-1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d] thiazol-2- ylamino)cyclohexanol 534.3, 1.78 88 209

(1R,2R)-2- (6-(2-(1-(2- (dimethylamino) ethyl)-1H- pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 479.2, 1.7789 209

(1R,2R)-2- (6-(2-(1-(2- (pyrrolidin-1-yl) ethyl)-1H- pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 505.2, 1.8090 209

(1R,2R)-2-(6- (2-(1-(2-(4- fluoropiperidin- 1-yl)ethyl)-1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d] thiazol-2- ylamino)cyclohexanol 537.2, 1.83 91 209

4-(2-(4-(4-(2- ((1R,2R)-2- hydroxycyclo- hexylamino) benzo[d]thiazol-6-yloxy)pyridin- 2-yl)-1H- pyrazol-1- yl)ethyl) piperazin-2-one 534.2,1.73 92 179

(1R,2R)-2-(6- (2-(1-((1,3- dioxolan-2-yl) methyl)-1H- pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 494.2, 1.9293 214

(S)-6-(2- chloropyridin-4- yloxy)-N-(1- (ethylsulfonyl) piperidin-3-yl)benzo[d] thiazol-2-amine 453.0, 2.59 94 217

(S)-6-(2- (1H-pyrazol-4- yl)pyridin-4- yloxy)-N-(1- (ethylsulfonyl)piperidin-3- yl)benzo[d] thiazol-2-amine 485.1; 1.73 95 217

(S)-N-(1- (ethylsulfonyl) piperidin-3-yl)- 6-(2-(1-propyl- 1H-pyrazol-4-yl)pyridin-4- yloxy)benzo[d] thiazol-2- amine 527.1; 2.24 96 217

(S)-N-(1- (ethylsulfonyl) piperidin-3-yl)- 6-(2-(1-(2- morpholinoethyl)-1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d] thiazol-2-amine 598.3; 1.6797 218

(S)-6-(2-(1-ethyl- 1H-pyrazol- 4-yl)pyridin-4- yloxy)-N-(1-(ethylsulfonyl) piperidin-3- yl)benzo[d] thiazol-2-amine 513.2; 1.89 98218

(S)-N-(1- (ethylsulfonyl) piperidin-3-yl)- 6-(2-(1-(2- fluoroethyl)-1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d] thiazol-2-amine 531.2, 1.87 99218

(S)-6-(2-(1-(2,2- difluoroethyl)- 1H-pyrazol-4- yl)pyridin-4-yloxy)-N-(1-(ethylsulfonyl) piperidin-3- yl)benzo[d] thiazol-2-amine 549.2;1.93 100 218

(S)-N-(1- (ethylsulfonyl) piperidin-3-yl)- 6-(2-(1-(2- methoxyethyl)-1H-pyrazol-4-yl) pyridin-4- yloxy)benzo[d] thiazol-2-amine 543.2; 2.10 101218

(S)-6-(2-(1-(2- (diethylamino)ethyl)- 1H-pyrazol-4-yl) pyridin-4-yloxy)-N-(1-(ethylsulfonyl) piperidin- 3-yl)benzo[d] thiazol-2-amine 589.2,1.94 102 177

(R)-4-methyl- 2-(6-(2-(4- methyl-1H- imidazol-2- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino) pentan-1-ol 424.2; 2.03 103

(R)-4-methyl- 2-(6-(2- (4,5,6,7- tetrahydro-1H- benzo[d]imidazol-2-yl)pyridin-4- yloxy)benzo[d] thiazol-2- ylamino) pentan-1-ol 104 219

(1R,2R)-2- (6-(pyridin-4- yloxy)benzo[d] thiazol-2-ylamino) cyclohexanol342.1; 1.74 105 207

(1R,2S)-1-(6- (6′-fluoro-2,3′- bipyridin-4- yloxy)benzo[d] thiazol-2-ylamino)-2,3- dihydro-1H- inden-2-ol 471.1; 2.32 106 207

(1R,2S)-1-(6-(6′- (dimethylamino)- 2,3- bipyridin-4- yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 496.1; 2.11 107

(1R,2S)-1-(6- (2-(4-methyl- 1H-imidazol-2-yl) pyridin-4- yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 108

(1R,2S)-1- (6-(2-(4,5- dimethyl-1H- imidazol-2- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 109

(1R,2S)-1-(6- (2-(5-ethyl-4- methyl-1H- imidazol-2- yl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 110

(1R,2S)-1-(6- (2-(4,5,6,7- tetrahydro-1H- benzo[d]imidazol-2-yl)pyridin-4- yloxy)benzo[d] thiazol-2-ylamino)- 2,3-dihydro-1H-inden-2-ol 111

(1R,2S)-1- (6-(2-(4- (trifluoromethyl)-1H- imidazol-2-yl) pyridin-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 112 216

(1R,2R)-2- (6-(2-(3- methoxyprop-1- ynyl)pyridin- 4-yloxy)benzo[d]thiazol-2- ylamino) cyclohexanol 410.1; 1.96 113 216

(1R,2R)-2- (6-(2-(3- (dimethylamino) prop-1- ynyl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino) cyclohexanol 423.2; 1.80 114 216

(1R,2R)- 2-(6-(2- (cyclopropylethynyl) pyridin- 4-yloxy)benzo[d]thiazol-2- ylamino) cyclohexanol 406.2; 2.04 115 215

(1R,2R)-2-(6-(2- ethynylpyridin-4- yloxy)benzo[d] thiazol-2- ylamino)cyclohexanol 366.1; 1.91 116 216

(1R,2S)-1- (6-(2-(3- methoxyprop-1- ynyl)pyridin- 4-yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 444.1; 2.26 117 216

(1R,2S)-1- (6-(2-(3- (dimethylamino) prop-1- ynyl)pyridin-4-yloxy)benzo[d] thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 457.1;2.05 118 216

(1R,2S)-1-(6-(2- (cyclopropylethynyl) pyridin- 4-yloxy)benzo[d]thiazol-2- ylamino)-2,3- dihydro-1H- inden-2-ol 440.0; 2.35 119 215

(1R,2S)-1-(6-(2- ethynylpyridin-4- yloxy)benzo[d] thiazol-2-ylamino)-2,3- dihydro-1H- inden-2-ol 400.1; 2.20

Each of the compounds listed in Table 2 were shown to have activity withrespect to inhibition of CSF-1R with an IC₅₀ of less than about 10 μM.Many of the compounds exhibited activity with an IC₅₀ of less than about1 μM, or less than about 0.1 μM, or less than about 0.01 μM with respectto CSF-1R inhibition. The compounds of Tables 3 and 4 were found to havean activity of less than 1 μM. As such, each of the compounds of Tables2, 3, and 4 is preferred individually and as a member of a group.

In addition to CSF-1R inhibitory activity, many of the compounds ofTables 2, 3, and 4 were also screened for Raf inhibition (according tobiochemical screens described in U.S. Ser. No. 10/405,945, which isentirely incorporated by reference), as well as other kinases, and shownto inhibit CSF-1R significantly greater (between about 2 and about 1,000fold greater) than Raf and other kinases screened. More particularly,many of the compounds screened had activity greater about 1 μM withrespect to Raf inhibition, whereas many of the same compounds exhibitedactivities with respect to CSF-1R at less than about 0.1 μM. As such,many of the compounds of Tables 2, 3, and 4 are potent and selectiveinhibitors of CSF-1R.

BIOLOGICAL EXAMPLES Biological Example 1 In Vitro Kinase Assays forColony Stimulating Factor-1 Receptor (CSF-1R)

The kinase activity of various protein tyrosine kinases can be measuredby providing ATP and a suitable peptide or protein tyrosine-containingsubstrate, and assaying the transfer of phosphate moiety to the tyrosineresidue. Recombinant protein corresponding to the cytoplasmic domain ofthe human CSF-1R was purchased from Invitrogen Corporation, Carlsbad,Calif. U.S.A. (#PV3249). For each assay, test compounds were seriallydiluted, starting at 25 μM with 3 fold dilutions, in DMSO in 384 wellplates then mixed with an appropriate kinase reaction buffer consistingof 50 mM Hepes, 5 mM MgCl₂, 10 mM MnCl₂, 0.1% BSA, pH 7.5, 1.0 mMdithiothreitol, 0.01% Tween 80 plus 1 μM ATP. Kinase protein and anappropriate biotinylated peptide substrate at 50 nM were added to give afinal volume of 20 μL, reactions were incubated for 2 hours at roomtemperature and stopped by the addition of 10 μL of 45 mM EDTA, 50 mMHepes pH 7.5. Added to the stopped reaction mix was 30 μL of PT66Alphascreen beads (Perkin Elmer, Boston, Mass., U.S.A.). The reactionwas incubated overnight and read on the Envision (Perkin Elmer).Phosphorylated peptide product was measured with the AlphaScreen system(Perkin Elmer) using acceptor beads coated with anti-phosphotyrosineantibody PT66 and donor beads coated with streptavidin that emit afluorescent signal at the 520-620 nM emission wave length if in closeproximity. The concentration of each compound for 50% inhibition (IC₅₀)was calculated by non-linear regression using XL Fit data analysissoftware.

CSF-1R kinase was assayed in 50 mM Hepes pH 7.0, 5 mM MgCl₂, 10 mMMnCl₂, 1 mM DTT, 1 mg/ml BSA, 1.0 μM ATP, and 0.05 μMbiotin-GGGGRPRAATF-NH₂ (SEQ ID NO:2) peptide substrate. CSF-1R kinasewas added at final concentration of 4 nM.

Biological Example 2 In Vitro Inhibition of CSF-1R Receptor TyrosinePhosphorylation

To test the inhibition of CSF-1R receptor tyrosine phosphorylation,HEK293H purchased from Invitrogen Cat. #11631017 cells transfected withthe full-length human CSF-1R receptor cloned in house into mammalianepisomal transfection vector were incubated for 1 h with serialdilutions of compounds starting at 10 μM with 3 fold dilutions and thenstimulated for 8 min with 50 ng/ml MCSF. After the supernatant wasremoved, the cells were lysed on ice with lysis buffer (150 mM NaCl, 20mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100 and NaF, proteaseand phosphatase inhibitors) and then shaken for 15-20 min at 4° C. Thelysate was then transferred to total CSF-1R antibody coated 96-wellplates that had already been blocked with 3% Blocker A from Mesoscalediscovery (MSD) for 2 hours and washed afterwards. Lysates wereincubated overnight at 4° C. and the plates were then washed 4× with MSDTris Wash Buffer. The SULFO-TAG anti-pTyr antibody from MSD was dilutedto 20 nM final in 1% Blocker A (MSD) solution and added to the washedplates and incubated for 1.5-2 h before addition of read buffer (MSD).The plates were read on the Sector 6000 instrument (MSD). Raw data wasimported in Abase and EC₅₀s calculated with XL-fit data analysissoftware.

Biological Example 3 CSF-1R Inhibitors in MNFS-60 Pk/Pd Model

Five million MNFS-60 cells were implanted in HBSS/matrigel solution s.q.in the right flank. Approximately 3 weeks following tumor cell injectiontumors were measured and selected mice were randomized (n=3 except forthe vehicle group, where n=6) into groups based on their tumor size.

Compounds that inhibited M-CSF mediated proliferation in MNFS-60 cellsand phosphorylation of CSF-1R with EC₅₀s<100 nM were tested in theMNFS-60 syngeneic tumor model (5×10⁶ where implanted subcutaneously inmatrigel and grown 3-4 weeks until they reached approximately 150 mm²).A single 100 mg/kg dose of representative compounds disclosed herein wasadministered to MNFS-60 tumored animals; plasma and tumor samples wereharvested at various time points after dosing starting at 1 h up to 24h.

Several of the compounds disclosed herein were shown to inhibit Tyr723phosphorylation of CSF-1R in tumor lysates at ≧50% compared to vehiclecontrol 4 hrs after dosing as determined by Western Blot.

Additionally, several of the compounds disclosed herein were tested in arapid onset severe arthritis mouse model (Terato, K. et al., Journal ofImmunology 148:2103-2108; 1992) and treatment started on day three afterinjection of the anti-collagen antibody cocktail followed by LPSstimulation. Throughout the 12 days of treatment with CSF-1R inhibitors,the extent of swelling in the paws and bone resorption severity wasscored. Significant attenuation of the swelling was not observed in thetreated compared to control group; however, there was a trend towardimprovement of bone resorption severity. There are no reports to datethat CSF-1R inhibitors are effective in this arthritis model. The onlysuccessful reduction of disease progression was reported for inhibitionby CSF-1R signaling with an Anti-MCSF antibody in a less severe, sloweronset arthritis mouse model (Campbell et al J. Leukoc. Biol. 68:144-150; 2000).

Biological Example 4 Inhibition of Raf Kinase Signaling in an In VitroBiochemical Assay

The inhibitory effect of compounds on Raf was determined using thefollowing biotinylated assay. The Raf kinase activity was measured byproviding ATP, a recombinant kinase inactive MEK substrate and assayingthe transfer of phosphate moiety to the MEK residue. Recombinant fulllength MEK with an inactivating K97R ATP binding site mutation(rendering kinase inactive) was expressed in E. coli and labelled withbiotin post purification. The MEK cDNA was subcloned with an N-terminal(His)₆ tag and expressed in E. coli and the recombinant MEK substratewas purified from E. coli lysate by nickel affinity chromatographyfollowed by anion exchange. The final MEK substrate preparation wasbiotinylated (Pierce EZ-Link Sulfo-NHS-LC-Biotin) and concentrated to11.25 μM. Recombinant Raf (including c-Raf and mutant B-Raf isoforms)was obtained by purification from sf9 insect cells infected with thecorresponding human Raf recombinant expression vectors. The recombinantRaf isoforms were purified via a Glu antibody interaction or by MetalIon Chromatography.

For each assay, the compound was serially diluted, starting at 25 μMwith 3-fold dilutions, in DMSO and then mixed with various Raf isoforms(0.50 nM each). The kinase inactive biotin-MEK substrate (50 nM) wasadded in reaction buffer plus ATP (1 μM). The reaction buffer contained30 mM Tris-HCL₂ pH 7.5, 10 mM MgCl₂, 2 mM DTT, 4 mM EDTA, 25 mMbeta-glycerophosphate, 5 mM MnCl₂, and 0.01% BSA/PBS. Reactions weresubsequently incubated for 2 hours at room temperature and stopped bythe addition of 0.5 M EDTA. Stopped reaction mixture was transferred toa neutradavin-coated plate (Pierce) and incubated for 1 hour.Phosphorylated product was measured with the DELFIA time-resolvedfluorescence system (Wallac), using a rabbit anti-p-MEK (Cell Signaling)as the primary antibody and europium labeled anti-rabbit as thesecondary antibody. Time resolved fluorescence can be read on a Wallac1232 DELFIA fluorometer. The concentration of the compound for 50%inhibition (IC₅₀) was calculated by non-linear regression using XL Fitdata analysis software.

Biological Example 5 Inhibition of cKIT and PDGFRb Kinase Signaling inan In Vitro Biochemical Assay

The IC50 values for the inhibition of RTKs were determined in thealphascreen format measuring the inhibition by compound of phosphatetransfer to a substrate by the respective enzyme. Briefly, therespective RTK domain purchased as human recombinant protein (cKITUpstate #14-559, PDGFRb Invitrogen #P3082) were incubated with serialdilutions of compound in the presence of substrate and ATPconcentrations within 3 times the Km of the enzyme.

The kinase domain of cKIT was assayed in 50 mM Hepes, pH=7.5, 5 mMMgCl2, 10 mM MnCl2, 1 mM DTT, 0.1% BSA with 0.06 uM biotinylated peptidesubstrate (GGLFDDPSYVNVQNL-NH2)(SEQ ID NO: 1) and 15 uM ATP (ATP KMapparent=15 uM). The kinase domain of PDGFRβ was assayed in 50 mM Hepes,pH=7.5, 20 mM MgCl2, 1 mM DTT, 0.1% BSA with 0.1 uM biotinylated peptidesubstrate (GGLFDDPSYVNVQNL-NH2)(SEQ ID NO: 1) and 10 uM ATP (ATP KMapparent=25 uM). Reactions were incubated at room temperature for 3 to 4hr and stopped with buffer (20 mM EDTA, 0.01% Tween-20 for both PDGFRband cKIT). Alphascreen PY20 beads were added to the stopped cKITreactions and PY20 Ab/Protein A Alphascreen beads were added to thePDGFRβ stopped reactions. Both reactions were incubated overnight andread on the Alphascreen reader. The concentration of compound for 50%inhibition (IC₅₀) was calculated employing non-linear regression usingXL-Fit data analysis software. As a control compound, staurosporine isrun in every assay and a Z′>0.5 is required to validate results.

Biological Example 6 Cell Viability Assay in MCSF Dependent MNFS60 Cells

Cell viability was assessed by Cell Titer Glo, Promega. MNFS60 (murineAML cells) were seeded in TC treated 96-well plates at a density of5,000 cells per well in RPMI-1640, 10% FBS, and 1% PenicillinStreptomycin prior to addition of compound. Test compounds were seriallydiluted (3 fold) in DMSO to 500× the final concentration. For eachconcentration of test compound, 2 μl (500×) aliquots of compound or 100%DMSO (control) were diluted in 500 μl of culture medium that contained2× final concentration of growth factor MCSF for 2× concentration andthen diluted 1× on the cells. Final concentration of MCSF is 10 ng/ml.Cells were incubated for 72 hrs at 37° C., 5% CO₂. After the incubation100 μl Cell Titer Glo is added to each well to determine viable cells.The assay was performed according to the manufacturer's instruction(Promega Corporation, Madison, Wis. USA). Each experimental conditionwas performed in triplicate. Raw data was imported in Abase and EC₅₀scalculated with XL-fit data analysis software. Relative light units ofwells that contained cells without MCSF in the media and as aconsequence didn't grow were defined as 100% inhibited.

Biological Example 7 Tumor Induced Osteolysis Model

Tumor-induced osteolysis (TIO) models have been shown to recapitulategross bone destruction seen in cancer patients with osteolytic tumormetastasis and have been reported extensively in both the bisphosphonateliterature and in conjunction with the testing of novel anti-osteolyticagents. Results from these studies correlate well with human clinicalactivity (Kim S-J et al., 2005, Canc. Res., 65(9): 3707; Corey, E etal., 2003, Clin. Canc. Res., 9:295; Alvarez, E. et al., 2003, Clin.Canc. Res., 9: 5705). The procedure includes injection of tumor cellsdirectly into the proximal tibia. Once the cells are established, theyproliferate and secrete factors that potentiate osteoclast activity,resulting in trabecular and cortical bone resorption. Animals aretreated with anti-resorptive agents following tumor cell implantationand bone destruction is measured in a number of ways at the end of thestudy.

The tumor cell lines utilized in this protocol are of human origin andrepresent tumor lines that have been previously modified such that theynow express the enzyme Luciferase in order to track tumor cells in theanimal using the Xenogen system. The strength of the light signal alsogives an indication of approximately how many tumor cells are located ata particular site.

Mice are injected subcutaneously with either 2.5 mg/kg flunixinmeglumine 30 minutes prior to cell inoculation to providepost-procedural analgesia. The mice are then be anesthetized byisoflurane inhalation (ketamine/xylazine injection may be used ifisoflurane is not available). Anesthetized animals are placed in thesupine position and following tumor cell aspiration into a 50 or 100 μlmicro-syringe fitted with a 26- or 27-gauge needle, the needle will beinserted through the cortex of the anterior tuberosity of the righttibia with a rotating “drill-like” movement to minimize the chance forcortical fracture. Successful passage of the needle through the cortexand into the marrow is indicated by loss of resistance against theforward movement of the needle. Once the bone cortex is traversed, 10-20μl of cell suspension (6×10^5 MDA-MB-231Luc breast carcinoma or 3×10^5PC-3MLuc prostate carcinoma cells) will be injected into the tibia bonemarrow. Animals will be observed to ensure uneventful recovery (warmingpad or lamp) until they have recovered from anesthesia.

Progression of tumor growth in the bone can be divided into five stages(Stages 0-4). The stages are defined as follows and can be monitored bycomparison to the uninjected (left) leg of the mouse:

Stage 0: normal, no sign of any change in the bone.

Stage 1: Equivocal or minimal lesion; cortex/architecture normal.

Stage 2: Definite lesion; minimal cortex/architecture disruption.

Stage 3: Large lesion; cortex/architecture disruption.

Stage 4: Gross destruction; no preservation of architecture, “latestage”. Animals reaching this stage will be taken off the study andeuthanized.

Photon imaging of the legs are used to assess the tumor growth at theinjection and remote sites during study using the Xenogen system toquantitate tumor cells in the tibia and confirm lack of leakage intoother areas. Radiograms of the legs are taken up to once a week throughthe end of the study using Faxitron X-ray Unit to assess cortical bonedestruction at the injection site. While using more invasive cell linessuch as the PC-3M-Luc, we monitor bone damage one to two weeks afterinjection and weekly thereafter. For cell lines that form lesions at aslower rate, such as the MDA-MB-231Luc, which does not manifest bonedamage until 4-5 weeks post-implantation, first radiographic images aretaken approximately 4 weeks after animals have been intratibiallyimplanted with cells to establish baseline controls and then once a weekto measure bone damage starting at a time point when lesions begin todevelop based on model development pilot studies. For example, in miceinjected with MDA-MB-231Luc, an image would be taken approximately 4weeks post-implantation, with weekly images thereafter.

Animals may be dosed with small molecules, monoclonal antibodies, orproteins once or twice daily, by any standard routes.

The endpoint of this study is the time point at which the majority ofuntreated (negative control) animals have reached late stage disease(Stage 4) and have been euthanized. At that point, the remaining animalsin the study are euthanized, regardless of the stage of their tumors.Studies last approximately 5-10 weeks depending on the cell line. Afterthe final x-ray is taken, blood is drawn from the animals by cardiacpuncture (for assaying serum bone markers; see below). Endpoint x-rayimages are then distributed to 5 volunteers who score each imageaccording to the scoring system detailed above. Scores for each mouseare averaged and expressed as mean osteolytic score or percent ofanimals with severe osteolysis (animals with scores greater than 2).

Biological Example 8 Mouse Trap5b Assay (IDS Inc., Fountain Hills,Ariz.)

This assay is a solid phase immunofixed enzyme activity assay for thedetermination of osteoclast-derived tartrate-resistant acid phosphatase5b in mouse serum samples. Trap5b is expressed by bone resorbingosteoclasts and secreted into the circulation. Thus, serum Trap5b isconsidered to be a useful marker of osteoclast activity, number and boneresorption.

The mouse Trap5b assay uses a polyclonal antibody prepared usingrecombinant mouse Trap5b as antigen. In the test, the antibody isincubated in anti-rabbit IgG-coated microtiter wells. After washing,standard, controls and diluted serum samples are incubated in the wells,and bound Trap5b activity is determined with a chromogenic substrate todevelop color. The reaction is stopped and the absorbance of thereaction mixture read in a microtiter plate reader at 405 nm. Colorintensity is directly proportional to the amount and activity of Trap5bpresent in the sample. By plotting the mean absorbance for each standardon the ordinate against concentration on the abscissa, values forunknown samples can be read from the standard curve and expressed in U/LTrap5b. Analytical sensitivity of the assay is 0.1 U/L and inter- andintra-assay variation are below 10%. Trap5b levels were found tocorrelate well with mean osteolytic score (assessed by x-ray).

While a number of preferred embodiments of the invention and variationsthereof have been described in detail, other modifications and methodsof use will be readily apparent to those of skill in the art.Accordingly, it should be understood that various applications,modifications and substitutions may be made of equivalents withoutdeparting from the spirit of the invention or the scope of the claims.

The percent inhibition activities of the compounds of Tables 2, 3, and 4when tested at about 1 μM in the indicated assay as described in theBiological Examples are shown respectively in Tables 5, 6, and 7. It iscontemplated that compounds having 0% inhibition at 1 μM will exhibitinhibitory activities at a higher concentration. An “N/D” means that thecompound was not tested in the particular assay.

TABLE 5 Activities of the compounds of Table 2 Cmpd PDGFRβ CSF-1R cKitM-NFS-60 CP pCSF1R 1 N/D 99 N/D 21 N/D 2 N/D 100 N/D 63 80 3 N/D 96 N/D0 N/D 4 N/D 100 N/D 100 91 5 N/D 99 N/D 100 93 6 N/D 85 N/D N/D N/D 7N/D 94 N/D 17 21 8 N/D 99 N/D 60 92 9 N/D 99 N/D 58 75 10 35 99 N/D 6279 11 96 99 N/D 26 N/D 12 12 99 N/D 30 N/D 13 65 99 N/D 76 75 14 85 99N/D 56 71 15 88 100 N/D 97 92 16 20 99 N/D 25 81 17 10 100 85 81 94 1835 100 N/D 91 74 19 2 100 N/D 36 N/D 20 0 15 N/D N/D N/D 21 0 99 N/D 5565 22 0 21 N/D N/D N/D 23 0 50 N/D N/D N/D 24 20 99 N/D 12 N/D 25 7 98N/D 42 35 26 100 98 N/D 24 N/D 27 28 99 N/D 97 96 28 98 99 N/D 98 88 2951 99 N/D 0 N/D 30 14 25 N/D N/D N/D 31 N/D 100 18 57 79 32 22 100 N/D70 93 33 35 98 N/D 35 83 34 89 99 N/D 68 65 35 9 19 N/D N/D N/D 36 6 780 N/D N/D 37 16 79 N/D N/D N/D 38 14 34 N/D N/D N/D 39 10 67 N/D N/D N/D40 6 99 N/D 0 N/D 41 30 100 N/D 100 94 42 12 99 N/D 100 97 43 15 26 N/DN/D N/D 44 15 37 N/D N/D N/D 45 14 11 N/D N/D N/D 46 15 94 N/D 1 N/D 4712 13 N/D N/D N/D 48 0 84 N/D 0 N/D 49 25 55 63 N/D N/D 50 8 56 59 N/DN/D 51 2 95 40 N/D N/D 52 50 100 12 56 71 53 0 95 21 N/D N/D 54 7 100 1764 60 55 11 97 21 N/D N/D 56 0 66 55 N/D N/D 57 3 97 35 35 N/D 58 85 9848 30 N/D 59 0 97 21 N/D N/D 60 2 92 6 N/D N/D 61 0 94 74 35 N/D 62 5 197 N/D N/D 63 3 45 6 N/D N/D 64 21 77 0 N/D N/D 65 38 99 98 100 97 66 37100 55 18 37 67 1 97 8 10 0 68 3 99 6 18 N/D 69 0 100 0 0 N/D 70 0 99 00 N/D 71 0 100 27 11 N/D 72 0 100 65 48 N/D 73 2 100 21 0 N/D 74 31 10034 14 N/D 75 0 99 7 0 N/D 76 0 98 9 0 N/D 77 15 100 92 79 94 78 0 87 9N/D N/D 79 0 100 31 57 94 80 0 87 7 N/D N/D 81 0 54 16 N/D N/D 82 0 46 9N/D N/D 83 0 99 12 26 N/D 84 0 99 12 32 44 85 N/D 99 79 100 98 87 N/D 9942 21 N/D 88 N/D 100 98 100 96 90 N/D 99 22 18 N/D 91 N/D 99 93 87 97 92N/D 99 98 17 N/D 94 N/D 99 14 28 N/D 95 8 98 40 N/D N/D 96 3 99 33 75 8997 5 99 99 67 84 98 0 26 7 N/D N/D 99 9 63 12 N/D N/D 100 9 99 10 N/DN/D 101 91 99 85 85 91 102 0 83 14 N/D N/D 103 14 60 8 N/D N/D 104 10 9918 47 63 105 8 99 22 49 70 106 0 99 2 N/D N/D 107 0 67 8 N/D N/D 108 4099 100 100 98 109 75 100 53 81 90 110 8 85 16 N/D N/D 111 2 25 15 N/DN/D 112 5 28 0 N/D N/D 113 17 97 7 19 N/D 114 15 100 92 36 N/D 115 18 9988 21 N/D 116 18 100 100 10 N/D 117 0 100 96 61 88 118 49 100 95 83 69119 32 99 18 13 N/D 120 0 75 5 N/D N/D 121 30 100 9 17 N/D 122 0 100 5319 N/D 123 2 99 15 0 N/D 124 0 99 32 51 94 125 0 100 35 44 45 126 99 6883 N/D N/D 127 20 100 81 95 95 128 83 100 90 95 95 129 34 99 92 94 92130 25 99 87 72 85 131 55 99 96 100 98 132 58 99 98 100 98 133 3 99 5345 92 134 0 98 98 93 93 135 20 100 68 96 91 136 84 100 88 100 97 137 98100 45 100 98 138 93 99 93 100 88 139 0 100 21 48 94 140 0 100 92 52 90141 0 100 1 22 N/D 142 97 99 98 100 88 143 4 99 33 97 91 144 100 99 100100 N/D 145 25 99 34 100 98 146 3 99 5 56 86 147 0 98 90 90 97 148 10099 99 100 98 149 0 99 4 67 92 150 1 99 34 49 87 151 0 99 5 26 N/D 152 8299 100 100 98 153 91 97 0 63 N/D 154 18 99 17 48 93 155 8 87 0 N/D N/D156 41 100 27 63 16 157 20 100 20 100 99 158 2 99 11 1 N/D 159 1 99 1217 N/D 160 18 99 13 30 N/D 161 94 100 0 38 N/D

TABLE 6 Activities of the compounds of Table 3 Cmpd PDGFRβ CSF-1R cKitM-NFS-60 CP pCSF1R 1 7 100 36 34 N/D 2 18 100 64 N/D N/D 3 0 100 14 8972 4 14 99 0 15 N/D 5 29 100 0 76 79 6 29 100 61 65 74 7 9 100 12 35 N/D8 31 95 99 0 N/D 9 84 100 14 2 N/D 10 9 67 0 N/D N/D 11 60 100 0 69 9212 1 95 0 N/D N/D 13 0 93 9 N/D N/D 14 0 96 3 N/D N/D 15 7 99 15 4 N/D16 9 99 12 30 N/D 17 12 99 19 23 N/D 18 23 99 80 22 N/D 19 0 96 8 23 N/D20 0 76 0 N/D N/D 21 7 100 64 11 N/D 22 21 100 6 36 N/D 23 20 57 48 34N/D 24 8 100 40 65 80 25 33 99 65 13 N/D 26 8 100 18 37 N/D 27 13 100 3871 95 28 6 100 20 53 83 29 12 100 64 48 72 30 12 100 25 28 N/D 31 20 10050 57 84 32 11 100 45 65 93 33 2 100 18 54 66 34 0 100 21 43 62 35 24100 59 56 57 36 24 100 73 85 80 37 0 55 19 N/D N/D 38 21 99 99 N/D N/D39 5 100 60 76 61 40 18 100 92 90 92 41 0 94 52 N/D N/D 42 6 100 4 44 8743 18 100 8 100 98 44 98 100 87 100 99 45 11 99 35 58 66 46 30 55 46 N/DN/D 47 4 100 0 55 83 48 16 99 14 26 49 12 100 21 33 77 50 14 99 13 18N/D 51 0 95 10 N/D N/D 52 47 100 61 47 N/D 53 96 100 100 100 N/D 54 65100 40 39 N/D 55 46 100 40 42 53 56 8 96 20 13 N/D 57 19 95 38 N/D N/D58 93 100 96 100 N/D 59 0 98 12 5 28 60 4 69 0 N/D N/D 61 12 95 3 N/DN/D 62 0 99 14 3 56 63 7 100 1 28 44 64 0 100 1 16 49 65 0 87 1 N/D N/D66 0 89 13 N/D N/D 67 0 55 7 N/D N/D 68 0 96 17 19 54 69 0 90 6 N/D N/D70 5 94 16 N/D N/D 71 1 75 13 N/D N/D 72 0 95 8 N/D N/D 73 5 96 13 N/DN/D 74 4 79 3 N/D N/D 75 2 76 11 N/D N/D 76 0 64 5 N/D N/D 77 2 88 7 N/DN/D 78 8 88 11 N/D N/D 79 0 99 6 22 34 80 14 99 0 8 19 81 6 100 71 9 1882 0 100 31 50 92 83 3 100 8 28 62 84 14 100 45 80 90 85 0 99 8 24 46 8632 63 15 N/D N/D 87 5 99 30 20 6 88 1 67 12 N/D N/D 89 2 100 15 15 65 9042 100 64 97 96 91 83 100 86 100 96 92 25 100 97 100 97 93 0 100 12 2347 94 9 100 90 17 38 95 2 100 0 60 65 96 0 70 29 N/D N/D 97 0 100 7 5059 98 0 60 6 N/D N/D 99 0 86 0 N/D N/D 100 6 81 0 N/D N/D 101 0 99 5 20N/D 102 9 100 0 75 88 103 7 95 0 N/D N/D 104 0 86 0 N/D N/D 105 6 100 731 N/D 107 99 100 19 100 96 108 4 100 10 70 94 109 16 100 13 67 N/D 1100 98 0 34 N/D 111 71 100 76 100 98 112 5 100 8 46 90 113 0 97 6 14 N/D114 0 100 4 86 97 115 55 100 18 97 82 116 0 100 21 41 N/D 117 48 100 7063 92 118 25 100 18 71 67 119 0 94 1 N/D N/D 120 0 65 0 N/D N/D 121 0 614 N/D N/D 122 0 67 0 N/D N/D 123 0 62 1 N/D N/D 124 10 99 0 18 N/D 125 999 2 17 N/D 126 83 100 36 100 97 127 0 95 0 N/D N/D 128 20 100 29 82 88129 99 100 99 N/D N/D 130 70 100 90 79 N/D 131 23 100 35 98 96 132 30 8018 N/D N/D 133 14 67 19 N/D N/D 134 13 53 11 N/D N/D 135 11 75 21 N/DN/D 136 0 86 3 N/D N/D 137 2 71 8 N/D N/D 138 37 100 100 105 N/D 139 19100 24 46 88 140 100 100 27 25 N/D 141 80 100 100 100 99 142 84 100 10097 96 143 22 100 63 80 90 144 12 100 38 41 N/D 145 33 100 39 58 86 146 8100 24 32 N/D 147 100 100 93 100 97 148 2 96 23 1 N/D 149 21 100 29 48N/D 150 2 100 24 22 N/D 151 38 100 46 43 N/D 152 21 97 25 13 N/D 153 2397 17 15 N/D 154 95 100 96 86 83 155 18 99 34 0 N/D 156 3 100 36 33 N/D157 17 100 43 42 N/D 158 1 99 27 0 N/D 159 23 100 29 98 96 160 19 100 9530 N/D 161 26 54 20 N/D N/D 162 30 100 20 100 99 163 39 100 32 100 99164 87 100 79 100 100 165 83 100 83 100 98 166 0 100 13 49 78 167 0 10016 24 N/D 168 43 100 40 100 99 169 0 75 12 N/D N/D 170 23 100 28 100 96171 18 100 25 96 95 172 18 100 22 100 97 173 8 100 18 52 81 174 3 86 18N/D N/D 175 1 100 11 17 N/D 176 0 63 12 N/D N/D 177 0 67 15 N/D N/D 178−3 82 17 N/D N/D 179 16 98 10 27 N/D 180 12 100 23 96 93 181 17 72 27N/D N/D 182 4 100 16 100 98 183 99 100 100 100 98 184 84 100 45 100 95185 29 100 32 100 94 186 14 100 13 100 99 187 25 100 32 100 98 188 35100 55 38 N/D 189 23 100 31 26 N/D 190 19 98 22 5 N/D 191 15 45 19 N/DN/D 192 22 99 56 14 N/D 193 15 95 27 0 N/D 194 16 77 20 N/D N/D 195 2581 90 N/D N/D 196 23 100 29 100 98 197 89 100 93 100 98 198 39 100 48100 94 199 81 100 61 100 97 200 19 100 29 69 83 201 22 52 17 N/D N/D 20219 100 32 17 N/D 203 15 98 22 20 N/D 204 74 100 92 85 N/D 205 39 100 2496 93 206 98 100 100 100 N/D 207 72 100 36 100 98 208 80 100 99 83 N/D209 1 100 17 36 N/D 210 26 100 19 26 N/D 211 50 100 85 23 N/D 212 28 10037 97 94 213 0 100 30 34 N/D 214 13 100 30 60 76 215 80 100 100 86 N/D216 45 100 59 98 93 217 23 99 16 0 N/D 218 23 100 28 16 N/D 219 85 10097 53 N/D 220 65 100 48 84 91 221 88 100 97 52 N/D 222 69 100 52 91 68223 28 100 54 100 97 224 0 100 26 33 N/D 225 0 90 21 N/D N/D 226 0 80 20N/D N/D 227 47 100 100 65 N/D 228 26 100 70 32 N/D 229 30 100 21 80 92230 14 100 6 58 65 231 49 100 9 100 99 232 64 100 34 100 99 233 84 10085 59 N/D 234 56 100 64 78 N/D 235 81 100 100 100 N/D 236 97 100 100 100N/D 237 13 100 24 100 94 238 90 100 100 100 N/D 239 25 100 100 90 N/D240 16 100 21 66 71 241 23 100 25 51 65 242 35 100 97 51 N/D 243 69 100100 76 N/D 244 35 100 25 67 85 245 21 100 16 53 81 246 82 100 100 100N/D 247 80 100 100 100 N/D 248 41 100 33 51 39 249 0 100 69 100 N/D 2500 97 98 20 N/D 251 28 100 56 80 74 252 6 100 100 81 N/D 253 6 100 100 86N/D 254 0 100 98 100 N/D 255 8 100 92 69 N/D 256 3 100 71 87 87 257 11100 100 100 N/D 258 62 100 44 100 99 259 6 100 24 100 98 260 0 100 25100 98 261 30 100 25 100 98 262 3 100 20 46 48 263 0 99 12 22 24 264 497 25 3 N/D 265 12 100 9 32 N/D 266 21 100 18 100 94 267 26 100 16 10096 268 29 100 25 84 87 269 13 100 18 75 85 270 11 98 21 50 74 271 24 9846 54 55 272 7 98 24 38 N/D 273 14 100 41 95 88 274 12 100 28 76 82 27516 100 45 89 94 276 26 100 39 100 97 277 5 100 26 24 N/D 278 12 100 3882 75 279 7 100 30 60 59 280 22 100 11 100 65 281 36 100 22 100 96 282 799 23 22 N/D 283 20 99 38 0 N/D 284 53 100 61 100 N/D 285 8 99 33 0 N/D286 0 100 23 71 94 287 20 100 57 35 N/D 288 24 100 78 70 N/D 289 2 99 280 N/D 290 15 100 10 2 N/D 291 0 48 4 N/D N/D 292 0 95 3 N/D N/D 293 0100 22 67 82 294 0 87 1 N/D N/D 295 0 85 5 N/D N/D 296 9 97 1 N/D N/D297 9 98 0 42 90 298 0 98 13 41 N/D 299 57 100 32 94 95 300 0 99 2 14N/D 301 7 55 0 N/D N/D 302 0 68 20 N/D N/D 303 12 74 24 N/D N/D 304 18100 9 23 N/D 305 7 87 15 N/D N/D 306 0 99 6 48 N/D 307 6 90 15 N/D N/D308 27 100 51 54 81 309 13 74 6 N/D N/D 310 13 15 13 N/D N/D 311 88 9322 N/D N/D 312 14 76 0 N/D N/D 313 2 52 23 N/D N/D 314 12 99 13 20 N/D315 0 98 17 27 N/D 316 12 99 8 41 98 317 12 100 70 50 95 318 13 100 4724 78 319 24 100 93 61 91 320 20 100 16 25 N/D 321 41 100 52 82 97 32211 99 18 21 N/D 323 24 100 25 100 98 324 19 99 21 15 N/D 325 43 100 2766 N/D 326 7 65 44 33 81 327 0 47 6 N/D N/D 328 0 100 14 63 80 329 17100 59 84 92 330 8 99 41 58 50 331 10 100 41 68 79 332 10 48 38 N/D N/D333 6 86 21 N/D N/D 334 15 100 20 67 71 335 0 100 21 57 50 336 14 94 2317 N/D 337 0 95 14 19 N/D 338 52 100 51 44 N/D 339 69 100 66 66 84 34098 100 100 100 96 341 88 100 99 99 96 342 61 100 84 75 87 343 28 100 5957 N/D 344 65 100 45 100 95 345 13 100 19 97 93 346 0 100 13 67 84 34758 100 37 100 99 348 55 100 47 100 90 349 73 100 77 100 N/D 350 91 100100 100 N/D 351 79 100 98 100 N/D 352 74 100 45 100 97 353 100 100 100100 N/D 354 98 100 100 100 N/D 355 27 100 27 100 99 356 99 100 100 100N/D 357 44 100 91 100 N/D 358 99 100 100 100 N/D 359 19 100 31 95 93 36016 100 29 100 98 361 75 100 100 N/D N/D 362 92 100 99 100 100 363 99 100100 N/D N/D 364 100 100 100 N/D N/D 365 79 100 100 100 97 366 26 100 94100 98 367 7 100 13 81 89 368 8 100 24 12 N/D 369 12 100 26 44 N/D 37034 100 64 60 81 371 9 100 29 69 79 372 8 100 21 75 88 373 0 101 51 10091 374 41 99 98 3 N/D 375 38 100 97 19 N/D 376 28 100 72 87 77 377 49100 75 93 N/D 378 43 100 62 90 87 379 36 77 16 N/D N/D 380 49 100 53 7994 381 20 100 30 100 99

TABLE 7 Activities of the compounds of Table 4 Cmpd PDGFRβ CSF-1R cKitM-NFS-60 CP pCSF1R 1 13 100 73 50 47 2 8 80 14 N/D N/D 3 1 100 15 67 854 0 100 29 92 94 5 8 100 18 91 92 6 26 100 26 100 99 7 5 100 23 54 N/D 835 100 25 100 98 9 45 100 15 100 98 10 9 100 6 76 83 11 4 100 8 38 N/D12 6 100 14 100 95 13 45 100 73 N/D N/D 14 85 100 71 N/D N/D 15 60 10059 100 99 16 59 100 41 100 100 17 72 100 61 100 100 18 28 100 45 100 10019 19 100 33 100 100 20 12 100 30 100 99 21 22 100 32 N/D N/D 22 90 10089 N/D N/D 23 0 100 29 7 N/D 24 0 100 26 100 100 25 1 100 33 100 86 26 0100 29 33 N/D 27 0 100 67 N/D N/D 28 0 100 98 N/D N/D 29 0 100 65 73 9030 0 100 18 73 93 31 0 96 26 N/D N/D 32 0 100 71 N/D N/D 33 0 100 65 10098 34 1 100 90 N/D N/D 35 90 100 46 100 98 36 26 100 45 5 N/D 37 24 10088 N/D N/D 38 16 100 27 100 99 39 9 100 98 N/D N/D 40 0 100 27 83 96 4119 100 66 100 97 42 28 100 28 100 99 43 0 95 14 N/D N/D 44 24 100 45 9453 45 44 100 53 100 99 46 42 100 24 100 99 47 31 100 55 58 79 48 98 10079 100 100 49 1 100 11 100 99 50 14 100 10 100 99 51 78 100 36 100 10052 42 100 27 100 100 53 14 100 12 100 99 54 1 100 11 100 99 55 2 100 11100 95 56 11 100 13 100 99 57 11 100 15 100 99 58 0 100 11 100 95 59 27100 25 100 99 60 0 100 9 100 99 61 23 100 3 100 98 62 27 100 5 97 97 6321 100 10 100 99 64 16 100 7 91 96 65 21 100 6 100 98 66 28 100 12 10099 67 42 100 97 100 98 68 100 100 57 100 99 69 28 100 12 100 99 70 86100 26 100 100 71 25 100 5 73 95 72 20 100 6 65 95 73 20 100 3 56 96 7422 100 0 60 97 75 10 99 0 0 N/D 76 15 100 8 95 96 77 25 100 6 100 99 7871 100 7 100 100 79 28 100 2 99 99 80 25 100 0 46 N/D 81 18 100 4 87 9782 24 100 2 92 99 83 36 100 7 100 99 84 30 100 11 100 97 85 53 100 13100 53 86 25 99 22 85 60 87 N/D 100 19 N/D N/D 88 N/D 100 14 N/D N/D 89N/D 100 18 N/D N/D 90 N/D 100 18 N/D N/D 91 N/D 100 17 N/D N/D 92 N/D100 15 N/D N/D 93 N/D 99 5 N/D N/D 94 N/D 100 12 N/D N/D 95 N/D 100 42N/D N/D 96 N/D 100 7 N/D N/D 97 N/D 100 14 N/D N/D 98 N/D 100 8 N/D N/D99 N/D 100 0 N/D N/D 100 N/D 100 5 N/D N/D 101 N/D 100 10 N/D N/D 102N/D 100 18 N/D N/D 103 N/D N/D N/D N/D N/D 104 N/D 100 4 N/D N/D 105 N/D100 10 N/D N/D 106 N/D 100 17 N/D N/D 107 N/D N/D N/D N/D N/D 108 N/DN/D N/D N/D N/D 109 N/D N/D N/D N/D N/D 110 N/D N/D N/D N/D N/D 111 N/DN/D N/D N/D N/D 112 N/D 100 11 N/D N/D 113 N/D 92 10 N/D N/D 114 N/D 1006 N/D N/D 115 N/D 95 12 N/D N/D 116 N/D 100 13 N/D N/D 117 N/D 100 11N/D N/D 118 N/D 100 11 N/D N/D 119 N/D 95 16 N/D N/D

The following references are cited in the specification.

-   Sherr, C. J., et al., The c-fms proto-oncogene product is related to    the receptor for the mononuclear phagocyte growth factor, CSF 1.    Cell, 1985. 41(3): p. 665-676.-   Roussel, M. F., et al., Transforming potential of the c-fms    proto-oncogene (CSF-1 receptor). 1987. 326(6104): p. 549-552.-   Lee, P. S., et al., The Cbl protooncoprotein stimulates CSF-1    receptor multiubiquitination and endocytosis, and attenuates    macrophage proliferation. Embo J, 1999. 18(13): p. 3616-28.-   Inaba, T., et al., Expression of M-CSF receptor encoded by c-fms on    smooth muscle cells derived from arteriosclerotic lesion. J Biol    Chem, 1992. 267(8): p. 5693-9.-   Baker, A. H., et al., Expression of the colony-stimulating factor 1    receptor in B lymphocytes. Oncogene, 1993. 8(2): p. 371-8.-   Sawada, M., et al., Activation and proliferation of the isolated    microglia by colony stimulating factor-1 and possible involvement of    protein kinase C. Brain Res, 1990. 509(1): p. 119-24.-   Stanley, E. R., et al., Biology and action of colony-stimulating    factor-1. Mol Reprod Dev, 1997. 46(1): p. 4-10.-   Bourette, R. P. and L. R. Rohrschneider, Early events in M-CSF    receptor signaling. Growth Factors, 2000, 17(3): p. 155-66.-   Pollard, J. W., Role of colony-stimulating factor-1 in reproduction    and development. Mol Reprod Dev, 1997. 46(1): p. 54-60; discussion    60-1.-   Dai, X. M., et al., Targeted disruption of the mouse    colony-stimulating factor 1 receptor gene results in osteopetrosis,    mononuclear phagocyte deficiency, increased primitive progenitor    cell frequencies, and reproductive defects. Blood, 2002. 99(1): p.    111-20.-   Scholl, S. M., et al., Anti-colony-stimulating factor-1 antibody    staining in primary breast adenocarcinomas correlates with marked    inflammatory cell infiltrates and prognosis. J Natl Cancer    Inst, 1994. 86(2): p. 120-6.-   Kacinski, B. M., CSF-1 and its receptor in breast carcinomas and    neoplasms of the female reproductive tract. Mol Reprod Dev, 1997.    46(1): p. 71-4.-   Ngan, H. Y., et al., Proto-oncogenes and p53 protein expression in    normal cervical stratified squamous epithelium and cervical    intra-epithelial neoplasia. Eur J Cancer, 1999. 35(10): p. 1546-50.-   Kirma, N., et al., Elevated expression of the oncogene c-fms and its    ligand, the macrophage colony-stimulating factor-1, in cervical    cancer and the role of transforming growth factor-beta1 in inducing    c-fms expression. Cancer Res, 2007. 67(5): p. 1918-26.-   Ridge, S. A., et al., FMS mutations in myelodysplastic, leukemic,    and normal subjects. Proc Natl Acad Sci USA, 1990. 87(4): p.    1377-80.-   Abu-Duhier, F. M., et al., Mutational analysis of class III receptor    tyrosine kinases (C-KIT, C-FMS, FLT3) in idiopathic myelofibrosis.    Br J Haematol, 2003. 120(3): p. 464-70.-   Yang, D. H., et al., The relationship between point mutation and    abnormal expression of c-fms oncogene in hepatocellular carcinoma.    Hepatobiliary Pancreat Dis Int, 2004. 3(1): p. 86-9.-   West, R. B., et al., A landscape effect in tenosynovial giant-cell    tumor from activation of CSF1 expression by a translocation in a    minority of tumor cells. Proc Natl Acad Sci USA, 2006. 103(3): p.    690-5.-   Tanaka, S., et al., Macrophage colony-stimulating factor is    indispensable for both proliferation and differentiation of    osteoclast progenitors. J Clin Invest, 1993. 91(1): p. 257-63.-   Choueiri, M. B., et al., The central role of osteoblasts in the    metastasis of prostate cancer. Cancer Metastasis Rev, 2006.    25(4): p. 601-9.-   Vessella, R. L. and E. Corey, Targeting factors involved in bone    remodeling as treatment strategies in prostate cancer bone    metastasis. Clin Cancer Res, 2006. 12(20 Pt 2): p. 6285s-6290s.-   Bingle, L., N. J. Brown, and C. E. Lewis, The role of    tumour-associated macrophages in tumour progression: implications    for new anticancer therapies. J Pathol, 2002. 196(3): p. 254-65.-   Pollard, J. W., Tumour-educated macrophages promote tumour    progression and metastasis. Nat Rev Cancer, 2004. 4(1): p. 71-8.-   Zins, K., et al., Colon Cancer Cell-Derived Tumor Necrosis    Factor-{alpha} Mediates the Tumor Growth-Promoting Response in    Macrophages by Up-regulating the Colony-Stimulating Factor-1    Pathway10.1158/0008-5472. CAN-06-2295. Cancer Res, 2007. 67(3): p.    1038-1045.-   Paulus, P., et al., Colony-Stimulating Factor-1 Antibody Reverses    Chemoresistance in Human MCF-7 Breast Cancer    Xenografts10.1158/0008-5472. CAN-05-3523. Cancer Res, 2006.    66(8): p. 4349-4356.-   Balkwill, F., K. A. Charles, and A. Mantovani, Smoldering and    polarized inflammation in the initiation and promotion of malignant    disease. Cancer Cell, 2005. 7(3): p. 211-7.-   Mantovani, A., et al., The chemokine system in diverse forms of    macrophage activation and polarization. Trends Immunol, 2004.    25(12): p. 677-86.-   Balkwill, F., TNF-alpha in promotion and progression of cancer.    Cancer Metastasis Rev, 2006. 25(3): p. 409-16.-   Cohen, M. S., et al., Structural bioinformatics-based design of    selective, irreversible kinase inhibitors. Science, 2005.    308(5726): p. 1318-21.-   Rabello, D., et al., CSF1 gene associated with aggressive    periodontitis in the Japanese population. Biochem Biophys Res    Commun, 2006. 347(3): p. 791-6.-   da Costa, C. E., et al., Presence of osteoclast-like multinucleated    giant cells in the bone and nonostotic lesions of Langerhans cell    histiocytosis. J Exp Med, 2005. 201(5): p. 687-93.-   Cenci, S., et al., M-CSF neutralization and egr-1 deficiency prevent    ovariectomy-induced bone loss. J Clin Invest, 2000. 105(9): p.    1279-87.-   Roggia, C., et al., Role of TNF-alpha producing T-cells in bone loss    induced by estrogen deficiency. Minerva Med, 2004. 95(2): p. 125-32.-   Kitaura, H., et al., M-CSF mediates TNF-induced inflammatory    osteolysis. J Clin Invest, 2005. 115(12): p. 3418-27.-   Daroszewska, A. and S. H. Ralston, Mechanisms of disease: genetics    of Paget's disease of bone and related disorders. Nat Clin Pract    Rheumatol, 2006. 2(5): p. 270-7.-   Lester, J. E., et al., Current management of treatment-induced bone    loss in women with breast cancer treated in the United Kingdom. Br J    Cancer, 2006. 94(1): p. 30-5.-   Lester, J., et al., The causes and treatment of bone loss associated    with carcinoma of the breast. Cancer Treat Rev, 2005. 31(2): p.    115-42.-   Stoch, S. A., et al., Bone loss in men with prostate cancer treated    with gonadotropin-releasing hormone agonists. J Clin Endocrinol    Metab, 2001. 86(6): p. 2787-91.-   Drees, P., et al., Mechanisms of disease: Molecular insights into    aseptic loosening of orthopedic implants. Nat Clin Pract    Rheumatol, 2007. 3(3): p. 165-71.-   Guzman-Clark, J. R., et al., Barriers in the management of    glucocorticoid-induced osteoporosis. Arthritis Rheum, 2007.    57(1): p. 140-6.-   Feldstein, A. C., et al., Practice patterns in patients at risk for    glucocorticoid-induced osteoporosis. Osteoporos Int, 2005.    16(12): p. 2168-74.-   Ritchlin, C. T., et al., Mechanisms of TNF-alpha-and RANKL-mediated    osteoclastogenesis and bone resorption in psoriatic arthritis. J    Clin Invest, 2003. 111(6): p. 821-31.-   Campbell, I. K., et al., The colony-stimulating factors and    collagen-induced arthritis: exacerbation of disease by M-CSF and    G-CSF and requirement for endogenous M-CSF. J Leukoc Biol, 2000.    68(1): p. 144-50.-   Saitoh, T., et al., Clinical significance of increased plasma    concentration of macrophage colony-stimulating factor in patients    with angina pectoris. J Am Coll Cardiol, 2000. 35(3): p. 655-65.-   Ikonomidis, I., et al., Increased circulating C-reactive protein and    macrophage-colony stimulating factor are complementary predictors of    long-term outcome in patients with chronic coronary artery disease.    Eur Heart J, 2005. 26(16): p. 1618-24.-   Murayama, T., et al., Intraperitoneal administration of anti-c-fms    monoclonal antibody prevents initial events of atherogenesis but    does not reduce the size of advanced lesions in apolipoprotein    E-deficient mice. Circulation, 1999. 99(13): p. 1740-6.-   Hao, A. J., S. T. Dheen, and E. A. Ling, Expression of macrophage    colony-stimulating factor and its receptor in microglia activation    is linked to teratogen-induced neuronal damage. Neuroscience, 2002.    112(4): p. 889-900.-   Murphy, G. M., Jr., L. Yang, and B. Cordell, Macrophage    colony-stimulating factor augments beta-amyloid-induced    interleukin-1, interleukin-6, and nitric oxide production by    microglial cells. J Biol Chem, 1998. 273(33): p. 20967-71.-   Murphy, G. M., Jr., et al., Expression of macrophage    colony-stimulating factor receptor is increased in the    AbetaPP(V717F) transgenic mouse model of Alzheimer's disease. Am J    Pathol, 2000. 157(3): p. 895-904.-   Kaku, M., et al., Amyloid beta protein deposition and neuron loss in    osteopetrotic (op/op) mice. Brain Res Brain Res Protoc, 2003.    12(2): p. 104-8.

1. A method of treating a CSF-1R mediated disorder wherein the disorderis osteoporosis in a human or animal subject, comprising administeringto the human or animal subject compound of Formula (I) or apharmaceutically acceptable salt thereof

effective to inhibit CSF-1R activity in the human or animal subject,wherein wherein X is O, S, or S(O); R¹ is

wherein the dashed lines are saturated bonds; wherein L is a covalentbond, alkylidene, or substituted alkylidene; and R¹⁰, R¹¹, and R¹² areindependently selected from the group consisting of hydrogen, halo,hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,and substituted amino; or R¹¹ is taken together with R¹² to form an arylring; R² is H or methyl; R³ is selected from the group consisting ofcarbonitrile, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, acyl, acylamino, carboxyl, carboxyl ester, substitutedsulfonyl, aminosulfonyl, and aminocarbonyl; each R⁶ is independentlyalkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substitutedamino, or halo; n is 0, 1, or 2; and when X is O, R⁴ is hydrogen,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substitutedalkynyl, and R⁵ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aminocarbonyl, halo,heteroaryl, substituted heteroaryl, cycloalkyl, or substitutedcycloalkyl; and when X is S or S(O), R⁴ is hydrogen, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and R⁵ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aminocarbonyl, halo, heteroaryl,substituted heteroaryl, cycloalkyl, or substituted cycloalkyl.
 2. Amethod of claim 1, wherein said compound selectively inhibits CSF-1R. 3.A method of claim 1, wherein the composition further comprises at leastone additional agent for treating the CSF-1R mediated disorder.
 4. Amethod of inhibiting CSF-1R comprising contacting a cell with a compoundof claim
 1. 5. The method of any one of claims 1-2 and 3 wherein thecompound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 4wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.